Synthetic techniques and intermediates for polyhydroxy dienyl lactones and mimics thereof

ABSTRACT

Synthetic methods and intermediates useful in the preparation of lactone containing compounds such as discodermolide and compounds which mimic the chemical or biological activity of discodermolide are provided.

RELATED APPLICATIONS DATA

This application is a continuation of U.S. patent application Ser. No.09/730,929, filed Dec. 6, 2000, which is a continuation-in-part of U.S.patent application Ser. No. 09/455,649, filed Dec. 7, 1999, now U.S.Pat. No. 6,242,616, which is a continuation-in-part of U.S. patentapplication Ser. No. 09/121,551, filed Jul. 23, 1998, now U.S. Pat. No.6,096,904, which is a continuation-in-part of U.S. patent applicationSer. No. 08/759,817, filed Dec. 3, 1996, now U.S. Pat. No. 5,789,605.

GOVERNMENT SUPPORT

Certain of the inventors were supported by National Institutes of HealthGrant GM-29028

FIELD OF THE INVENTION

This invention relates to lactone containing compounds such asdiscodermolide, to compounds which mimic the chemical and biologicalactivity thereof, and to methods and intermediates useful in theirpreparation.

BACKGROUND OF THE INVENTION

In 1990, Gunasekera and co-workers at the Harbor Branch OceanographicInstitute reported the isolation of (+)-discodermolide (1), anarchitecturally novel metabolite of the marine sponge Discodermiadissoluta (0.002% w/w). (See, Gunasekera, et al., J. Org. Chem. 1990,55, 4912. Correction: J. Org. Chem. 1991, 56, 1346).

Initial studies revealed that (+)-discodermolide suppresses both thetwo-way mixed-lymphocyte reaction and the concanavalin A-inducedmitogenesis of murine splenocytes in vitro with no associatedcytotoxicity. Moreover, (+)-1 suppresses the in vivo graft-vs.-hostsplenomegaly response induced by injection of parental splenocytes intoF1 recipient mice, with potency intermediate between those ofcyclosporin A and FK506. (Longley, et al., Transplantation 1991, 52,650; Longley, et al., Transplantation 1991, 52, 656; Longley, et al.Ann. N.Y. Acad. Sci. 1993, 696, 94). These findings stimulated therecent discovery that (+)-1 arrests cell development at the M phase bybinding and stabilizing mitotic spindle microtubules; thusdiscodermolide resembles taxol in its mode of action, but themicrotubule binding affinity of 1 is much higher. (ter Haar, et al.,Biochemistry 1996, 35, 243; Hung, et al., Chemi. & Biol. 1996, 3, 287).These and other results suggest that (+)-discodermolide holdsconsiderable promise as an anticancer agent. The scarcity of naturalmaterial however has precluded a complete evaluation of its biologicalprofile.

The absolute configuration of discodermolide remained undefined untilSchreiber et al. synthesized both antipodes of 1. (Nerenberg, et al. J.Am. Chem. Soc. 1993, 115, 12621; Hung, et al., Chem. & Biol. 1994, 1,67). Interestingly, the unnatural (−) antipode also displays significantimmunosuppressant activity.

There is, therefore, a need for improved synthetic methods for thepreparation of polyhydroxy, dienyl lactones such as the discodermolides,as well as a need for compounds having similar chemical and/orbiological activity.

OBJECTS OF THE INVENTION

It is one object of the present invention to provide polyhydroxy, dienyllactones and mimics thereof.

It is a further object to provide processes for the preparation of suchcompounds and their mimics.

It is another object of this invention to provide intermediates usefulin such processes.

SUMMARY OF THE INVENTION

These and other objects are satisfied by the present invention, which,in one aspect, provides synthetic methods for the discodermolides andother polyhydroxylactones. In preferred embodiments, such methodsinvolve contacting a phosphonium salt of formula I:

with base and an alkylthiol of formula II:

to form a diene of formula III:

wherein:

-   -   R₁, R₂, R₃, R₇, R₈, R₁₁, R₁₂ and R₁₃ are, independently, C₁-C₁₀        alkyl;    -   R₆ is H or C₁-C₁₀ alkyl;    -   X is a halogen;    -   Z, Z₁ and Z₂ are, independently, O, S or NR′;    -   R₄, R₉, R₁₄, and R₁₅ are, independently, acid labile hydroxyl        protecting groups;    -   R₅ is C₆-C₁₄ aryl;    -   Y is O, S or NR′;    -   R′ and R₁₆ are, independently, hydrogen or C₁-C₆ alkyl; and    -   R₁₈ is C₆-C₁₄ aryl.

In another embodiment, compounds of formula I are contacted withcompounds of the following formula XXIII:

to form a diene of formula XXXXX:

In another aspect, the methods of the invention involve producing analkene of formula IV.

This can be accomplished by contacting an organometallic reagent offormula Va:

with a vinyl halide of formula VIa:

wherein M is Li, Cu, Mg, or Zn and R₁₀ is an acid stable hydroxylprotecting group and all other variables are as defined above.Alternatively, a vinyl halide of formula Vb:

can be contacted with an organometallic compound of formula VIb:

In yet another aspect, the methods of the invention involve compoundshaving formula VII.

by contacting a diene of formula VIIIa:

with an organometallic compound having formula Va wherein R₂₄ ishydrogen and R₂₅ is hydrogen or an acid stable hydroxyl protectinggroup. Alternatively, an organometallic compound having formula VIIIbcan be contacted with a vinyl halide having formula Vb.

The methods of the invention also involve producing dienes havingformula VIIIa by contacting phosphonium salts having formula IX:

with base and alkylthiol compounds having formula II.

The present invention also provides synthetic intermediates which areuseful in the preparation of polyhydroxylactones, including thecompounds having formulas I-IX and X:

wherein:

-   -   R₁₉, R₂₀, R₂₁ and R₂₂ are, independently, C₁-C₁₀ alkyl; and    -   R₂₃ is C₇-C₁₅ aralkyl.

The present invention also provides compounds which mimic the chemicaland/or biological activity of the discodermolides. In preferredembodiments, such compounds have formula XI:

where

-   -   R₃₀ is substituted or unsubstituted C₁-C₁₀ alkyl or a moiety        formula XII or XIII:    -   where A is C₁-C₂₀ alkyl, —CH₂NH (T) or a moiety of formula XIV:        wherein    -   T is peptide having 1 to about 10 amino acids;    -   R₃₂, R₄₀, R₄₂, R₄₃, R₄₆, R₄₇, and R₄₈ are, independently,        hydrogen or C₁-C₆ alkyl;    -   R₄₁ is a side chain of an amino acid;    -   W₁ and W₂ are, independently, —OR₄₉ or —NHP₁;    -   P₁ is hydrogen or an amine protecting group;    -   R₃₃ and R₃₆ are, independently, hydrogen, C₁-C₁₀ alkyl, —OR₅₀,        ═O or together form —CH₂—CH₂—;    -   R₃₄ and R₃₅ are, independently, hydrogen or together form        —C(H)═C(H)—C(H)═C(H)—;    -   R₃₉ is —OR₅₁ or —CH₂—R₅₁;    -   R₃₁ and R₄₄ are, independently, C₁-C₁₀ alkyl;    -   Q₁ and Q₂ are, independently, hydrogen, —OR_(Q), —NHR₅₂,        —OC(═O)NH₂ or together form —O—C(O)—NH—;    -   R_(Q) is hydrogen or a hydroxyl protecting group;    -   R₅₁ is substituted or unsubstituted C₆-C₁₄ aryl,        tetrahydropyranyl, furanosyl, pyranosyl (e.g.,        tetramethylfucosyl, tetramethylmannosyl, tetramethylgaractosyl        and tetramethylglucosyl), C₃-C₁₀ lactonyl or 2-pyranonyl;    -   R₄₅ is C₁-C₆ alkenyl, C₁-C₆ alkyl, C₆-C₁₄ aryl, C₂-C₁₀        heterocycloalkyl, C₃-C₁₀ cycloalkyl, or C₇-C₁₅ aralkyl; and    -   R₄₉, R₅₀, and R₅₂ are, independently, hydrogen or C₁-C₆ alkyl.

In another aspect, the present invention provides processes forpreparing amides having formula XX:

wherein Ar is C₆-C₁₄ aryl comprising the steps of contacting a compoundhaving formula XXI:

with a compound having formula XXII:

for a time and under conditions effective to form the amide.

Also provided are processes for producing compounds of formula XXIII:

comprising the steps of contacting an aldehyde of formula XXIV:

with an enol ether of formula XXV:

in the presence of a titanium salt for a time and under conditionseffective to form an enone of formula XXVI:

Such enones are then contacted with a reducing agent for a time andunder conditions effective to form a corresponding enol, which iscontacted with a compound having formula R-L (wherein L is a leavinggroup) for a time and under conditions effective to form a protectedenol. This protected enol is contacted with an oxidizing agent for atime and under conditions effective to oxidize the carbon-carbon doublebond of the protected enol.

The invention also provides processes for producing halogenated olefinsof formula XXVII:

by contacting an aldehyde of formula XXVIII:

with an α-halo sulfone of formula XXIX:

for a time and conditions effective to from the halogenated olefin.

Also provided are processes for producing halogenated olefins of formulaXXX:

comprising the steps of contacting a compound of formula XXXI:

with triphenylphosphine and a carbon tetrahalide for a time and underconditions effective to form a dihalogenated olefin of formula XXXII:

Such a dihalogenated olefin is contacted with an organometallic compound(such as lithium dimethyl cuprate or an alkylzinc compound such asmethyl zinc chloride or methyl zinc bromide)in the presence of a catalyst for a time and under conditions effectiveto form the halogenated olefin.

Additional processes of the invention are directed to synthesis ofdienes of formula XXXIII:

comprising contacting a phosphonium salt of formula XXXIV:

with a base and a compound of formula XXXV:

for a time and under conditions effective to form the diene.

The invention also provides processes for producing a compound offormula XXXVI:

comprising contacting a compound of the formula XXXVII:

wherein J is C₁-C₁₀ alkyl, C₆-C₁₄ aryl, C₆-C₁₄ alkaryl, C₆-C₁₄alkheteroaryl, C₂-C₁₀ heterocycloalkyl. or C₂-C₁₀ heterocycloalkenyl(preferably 4-methoxyphenyl, 4-hydroxyphenyl, 2-pyridyl, 3-pyridyl, or4-pyridyl) with a phosphonium salt of formula XXXIV:

and base.

The invention also provides synthetic intermediates having formulasXXXIII-XXXXV:

The present invention also provides methods for inhibiting mammaliancell proliferation by contacting mammalian cells with a compoundaccording to the invention or by administering a compound according tothe invention (or a pharmaceutical composition comprising such acompound) to a mammal suffering from undesired cell proliferation. Alsoprovided are methods for inhibiting rejection of a transplanted organ ina mammal comprising administering a compound or composition according tothe invention to a mammalian organ recipient.

The present invention also provides process for forming a halogenatedolefin of formula:

wherein:

-   -   R₆ is selected from H and C₁-C₆ alkyl;    -   R₇ and R₈ are independently C₁-C₁₀ alkyl;    -   R₉ is an acid labile hydroxyl protecting group;    -   R₁₀ is a protecting group labile to DDQ; and,    -   X is halogen;        the process comprising contacting an aldehyde of formula:        with a compound of formula R₆(R₁₈)₃PX and X₂ in the presence of        base, wherein R₁₈ is C₆-C₁₄ aryl, for a time and conditions        effective to form the halogenated olefin.

The present invention also provides a process for forming a triene offormula:

wherein:

-   -   R₁, R₂, R₇, and R₈ are independently C₁-C₁₀ alkyl;    -   R₃ and R₆ are independently selected from hydrogen and C₁-C₆        alkyl;    -   R₄ and R₉ are independently acid labile hydroxyl protecting        groups;    -   R₂₅ is an acid stable hydroxyl protecting group; and    -   R₁₀ is a hydroxyl protecting group;        the process comprising contacting an aldehyde of formula:        with a compound of formula Ph₂PCH₂CH═CH₂ in the presence of a        base and a compound of formula Ti(O—R₂₇)₄, wherein R₂₇ is        C_(1-C) ₆ alkyl; followed by treatment with R₂₈X wherein R₂₈ is        C₁₋₆ alkyl and X is a halogen, for a time and under conditions        effective to form the triene.

The present invention also provides a process comprising contacting atriene of formula:

with a compound of formula:

wherein X is a first halogen and R₂₆ is selected from C₆₋₁₄ aryl andC₁₋₆ alkyl, to form a triene alcohol of formula:

and;

-   -   contacting the triene alcohol with Y₂ in the presence of P(R₁₈)₃        and a base, wherein R₁₈ is C₆₋₁₄ aryl and Y is a second halogen,        under conditions to form a compound of formula:

The present invention also provides a process of forming an aldehyde offormula:

the process comprising contacting a compound of formula:

wherein:

-   -   R₁, R₂, R₇, and R₈ are independently C₁-C₁₀ alkyl;    -   R₃ and R₆ are independently selected from hydrogen and C₁-C₆        alkyl;    -   R₄ and R₉ are independently acid labile hydroxyl protecting        groups; and    -   R₁₀ is a trityl group;        with hydride to form an alcohol of formula:        and oxidizing the alcohol to form the aldehyde.

The present invention also provides a process for forming a tetraene offormula:

wherein:

-   -   R₁, R₂, R₇, and R₈ are independently C₁-C₁₀ alkyl;    -   R₃, R₆, and R₁₆ are independently selected from hydrogen and        C₁-C₆ alkyl;    -   R₄ and R₉ are independently an acid labile hydroxyl protecting        group;    -   R₂₅ is an acid stable hydroxyl protecting group; and    -   J is selected from:        alkaryl; and alkheteroaryl;        wherein    -   R₃₂ is H or C₁-C₆ alkyl and R₃₃ is an acid labile hydroxyl        protecting group;        the process comprising contacting a compound of the formula:        J-CHO        with a phosphonium salt of the formula:        wherein R₁₈ is C₆-C₁₄ aryl, in the presence of a base for a time        and under conditions effective to form the tetraene.

The present invention also provides a process for forming a tetraene offormula:

wherein:

-   -   R₁, R₂, R₇, and R₈ are independently C₁-C₁₀ alkyl;    -   R₃, R₆, and R₁₆ are independently selected from hydrogen and        C₁-C₆ alkyl; and    -   J is selected from:        alkaryl, and alkheteroaryl;        wherein    -   R₃₂ is H or C₁-C₆ alkyl and R₃₃ is H;        the process comprising contacting an alcohol of formula:        wherein R₄, R₉, and R₃₃ are acid labile hydroxyl protecting        groups, with an isocyanate of the formula:        X₃CC(═O)NCO        wherein X is a halogen, to form a carbamate intermediate;    -   contacting the carbamate intermediate with neutral alumina to        form a carbamate of formula:        and;    -   removing the acid labile hydroxyl protecting groups by        contacting the carbamate with acid in a protic solvent to form        the tetraene.

The present invention also provides several processes for forming analcohol of formula:

In one process, the process comprises contacting a compound of formula:

with a compound of formula:

wherein R₂₅ is an acid stable protecting hydroxyl protecting group, andR₃₅ is selected from C₄ alkyl and a halogen, in the presence of a metalcoupling catalyst for a time and under conditions effective to form acoupling product of formula:

and deprotecting the coupling product to form the alcohol.

In another process, the alcohol is formed by contacting a compound offormula:

wherein:

-   -   R₂₅ is an acid stable protecting hydroxyl protecting group;    -   R₃₅ is selected from CH₂P(R₁₈)₃X, CHO, —P(═O)Ph₂, and    -   X is a halogen; and    -   R₁₈ is C₆₋₁₄ aryl;        with a compound of formula:        J-R₃₅        in the presence of a base to form a coupling product of formula:        and deprotecting the coupling product to form the alcohol.

The present invention also provides a process for forming an alcohol offormula:

wherein:

-   -   R₇ and R₈ are independently C₁-C₁₀ alkyl;    -   R₁₀ is an acid stable hydroxyl protecting group;    -   R₃₄ is selected from (CH₂)_(n)C₆-C₁₄ aryl and (CH₂OCH₂)C₆-C₁₄        aryl, wherein the aryl is substituted with 0-3 R₃₅;    -   R₃₅ is selected from F, CF₃, Br, Cl, and NO₂; and    -   n is selected from 0 and 1;        the process comprising contacting a compound of formula:        with the enolate of a compound of formula:        in the presence of Lewis acid for a time and under conditions        effective to form the alcohol.

The present invention also provides intermediate compounds of formula:

wherein:

-   -   R₆ is C₁-C₄ alkyl;    -   R₇ and R₈ are independently C₁-C₁₀ alkyl;    -   R₉ is an acid labile hydroxyl protecting group;    -   R₁₀ is an acid stable hydroxyl protecting group; and    -   X is halogen.

The present invention also provides intermediate compounds of formula:

wherein:

-   -   R₁, R₂, R₇, and R₈ are independently C₁-C₁₀ alkyl;    -   R₃ and R₆ are independently selected from hydrogen and C₁-C₆        alkyl;    -   R₄ and R₉ are independently acid labile hydroxyl protecting        groups;    -   R₂₅ is an acid stable hydroxyl protecting group; and    -   R₁₀ is a trityl group; and    -   R₂₉ is selected from OH, CHO, and —CH═CH—CH═CH₂.

The present invention also provides a compound of formula:

wherein:

-   -   R₁, R₂, R₇, and R₈ are independently C₁-C₁₀ alkyl;    -   R₃, R₆, and R₁₆ are independently selected from hydrogen and        C₁-C₆ alkyl;    -   R₄, R₉, and R₁₄ are acid labile hydroxyl protecting groups;    -   R₄₀ is selected from OR₂₅ and OC(═O)NH₂;    -   R₂₅ is an acid stable protecting group; and    -   J is selected from:        alkaryl and alkheteroaryl;        wherein    -   R₃₂ is C₁-C₆ alkyl;    -   R₃₃ is selected from H and an acid labile hydroxy protecting        group; and    -   R₃₄ is C₁-C₆ alkyl.

BRIEF DESCRIPTION OF THE DRAWINGS

The numerous objects and advantages of the present invention may bebetter understood by those skilled in the art by reference to theaccompanying figures, in which:

FIG. 1 shows a retrosynthetic analysis for (−)- discodermolide 1.

FIG. 2 shows a synthetic scheme for compound (+)-5.

FIG. 3 shows a synthetic scheme for fragment A.

FIG. 4 shows a synthetic scheme for compound 22.

FIG. 5 shows a synthetic scheme for compound 39.

FIG. 6 shows a synthetic scheme for compounds 15 and 25.

FIG. 7 shows a synthetic scheme for compound 34.

FIG. 8 shows a synthetic scheme for fragment C.

FIG. 9 shows a synthetic scheme for fragment B.

FIG. 10 shows a synthetic scheme for compound 39.

FIG. 11 shows a synthetic scheme for compound 40.

FIG. 12 shows a synthetic scheme for compound 49.

FIG. 13 shows a synthetic scheme for compounds 53 and 46.

FIG. 14 shows a synthetic scheme for compound 56.

FIG. 15 shows a synthetic scheme for compound 1.

FIG. 16 shows a synthetic scheme for compound 104.

FIG. 17 shows a synthetic scheme for compound 107.

FIG. 18 shows a synthetic scheme for compound 206.

FIG. 19 shows a synthetic scheme for compound 212.

FIG. 20 shows a synthetic scheme for compound 217.

FIG. 21 shows a synthetic scheme for compound 305.

FIG. 22 shows a synthetic scheme for compound 309.

FIG. 23 shows a synthetic scheme for compound 401.

FIG. 24 shows a synthetic scheme for compound 501.

FIG. 25 shows a synthetic scheme for compound 601.

FIG. 26 shows a synthetic scheme for compound 701 R=alkyl).

FIG. 27 shows a synthetic scheme for compound 808.

FIG. 28 shows a synthetic scheme for compound 801.

FIG. 29 shows a synthetic scheme for compound 901.

FIG. 30 shows a synthetic scheme for compound 1003.

FIG. 31 shows a synthetic scheme for compound 1104(Ar=2,4-dimethyl-3-methoxyphenyl (a), 2-methyl-5-methoxyphenyl (b),2,4-dimethyl-5-methoxyphenyl (c), 2,4-dimethylphenyl (d), and4-methylphenyl (e)).

FIG. 32 shows a synthetic scheme for compound 1111.

FIGS. 33-36 show representative compounds of the invention.

FIG. 37 shows a synthetic scheme for compound (−)-5.

FIG. 38 shows a synthetic scheme for compound 67.

FIG. 39 shows a synthetic scheme for compound (+)-B.

FIG. 40 shows a synthetic scheme for compound 58.

FIG. 41 shows a synthetic scheme for compound 86.

FIG. 42 shows a synthetic scheme for compound 58.

FIG. 43 shows a synthetic scheme for compound (+)-B.

FIG. 44 shows a synthetic scheme for compound 89.

FIG. 45 shows a synthetic scheme for compound 75.

FIG. 46 shows a synthetic scheme for compound (+)-59.

FIG. 47 shows a synthetic scheme for (+)-discodermolide.

FIG. 48 shows a synthetic scheme for compound 95.

FIG. 49 shows a synthetic scheme for compound 94.

FIG. 50 shows a synthetic scheme for compound 58.

FIG. 51 shows a synthetic scheme for compound 1205

FIG. 52 shows a synthetic scheme for compound 1209

FIG. 53 shows a synthetic scheme for compound 1211

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

It has been found in accordance with the present invention that thesynthesis of polyhydroxy, dienyl lactones such as the discodermolidescan be achieved by highly convergent and stereocontrolled syntheticprocedures.

As shown in FIG. 1 for the (−)-discodermolide antipode, our analysisrevealed a repeating triad of contiguous stereocenters, separated byZ-olefinic linkages at C(8,9) and C(13,14). Disconnections at C(8,9),C(14,15) and C(21,22) generated fragments A, B and C, each deriving inturn from a common precursor (5) containing the recurring stereochemicaltriad.

As shown in FIG. 2, precursor 5 was prepared by a synthetic procedurewhereby hydroxy ester (−)-6 was protected as the p-methoxybenzyl (PMB)ether by treatment with the Bundle trichloroimidate reagent 7 underacidic conditions. Reduction with LiAlH₄ provided the alcohol (−)-8after distillation. Swern oxidation, Evans aldol condensation, andWeinreb amide formation completed the construction of common precursor(+) -5. This concise five-step synthesis could be routinely carried outon a 50-g scale in 59% overall yield.

Alternatively, as shown in FIG. 37, Swern oxidation of (+)-8 followed bythe addition norephedrine derived oxazolidinone 61 results in acrystalline product 62 which, in turn, can be converted to commonprecursor (−)-5.

In view of the polypropionate structure of the A fragment, we performeda second asymmetric aldol reaction, as shown in FIG. 3. Initialformation of the p-methoxybenzylidene acetal (−)-11 from commonprecursor (−)-5 (78% yield) was designed to allow selective deprotectionof C(21) and C(19) hydroxyls for introduction of the terminal diene andcarbamate moieties. Following reduction of amide (−)-11 to the aldehyde(80% yield), (aldol reaction with oxazolidinone (+)-9 (80% yield)provided alcohol (+)-13 which incorporated the five stereocenters ofsubunit A. The structure of (+)-13 was confirmed by single-crystal X-rayanalysis. Protection of the secondary alcohol as the TBS ether andremoval of the chiral auxiliary (LiBH₄, EtOH, THF) afforded primaryalcohol (−)-15 (81% yield, two steps), which could be efficientlyconverted either to tosylate (−)-16 or iodide (−)-A.

As outlined in FIG. 1, our strategy required a Z vinylic halide B forcoupling with fragment A. Beginning again with the common precursor(+)-5, TBS protection (FIG. 4) followed by reduction of the Weinrebamide [DIBAL (2 equiv), THF, −78°C.] (Kim, et al., Tetrahedron Lett.1989, 30, 6697) afforded aldehyde (+)-18 in 88% yield for the two steps.We adopted a stepwise approach to introduction of the vinyl halide,whereby (+)-18 was converted to the Z α-bromo unsaturated ester (−)-19(Ph₃PCBrCO₂Et, PhH, reflux; 75% yield after chromatography). Reductionto allylic alcohol (−)-20 followed by mesylation and displacement withLiBHEt₃ then furnished Z vinyl bromide (−)-22 in 77% overall yield from19.

One preferred synthetic strategy utilized a vinyl iodide as the desiredB segment. Synthesis of (−)-B was achieved by direct olefination ofaldehyde (+)-18 (41%, 6:1 Z/E) (FIG. 9), followed by chromatographicremoval of the undesired E product. Alternatively, the B segment can beprepared by the two routes shown in FIG. 39. The first involves anα-iodo sulfone 69 to effect a one-step installation of the vinyl iodide.The second exploits the enhanced reactivity of the trans iodide ofdiiodide 70.

Our preferred synthetic strategy involves selective removal of a primaryPMB ether in the presence of a PMP acetal in the AB coupling product((−)-39, FIG. 5). A 1:1 mixture of PMB ether (−)-22 and PMP acetal(−)-15 was exposed to DDQ (1.1 equiv) in CH₂Cl₂/H₂O (FIG. 6). The acetal(−)-15 largely remained intact while the debenzylated alcohol (−)-25 wasformed in 83% yield.

As shown in FIG. 7, we again utilized the TBS ether (+)-17 for thepreparation of C from common precursor (+)-5. Oxidative cleavage of thePMB group (DDQ, CH₂Cl₂, H₂O) provided alcohol 26 in variable (60-86%)yields, accompanied by the corresponding lactone. Hydrogenolysis withPearlman's catalyst afforded (+)-26 in 92% yield. Exposure of thealcohol to SO₃.pyr furnished aldehyde (+)-27 (98% yield), which in turnwas converted to dithiane (+)-28 (79%). In the latter step, ourmodification of the Evans protocol for dithiane generation[(TMSSCH₂)₂CH₂, ZnCl₂, Et₂O] minimized elimination of the TBS ether toform the α,β-unsaturated amide. Following reduction to aldehyde (+)-29with DIBAL (91% yield), dimethyl acetal formation gave (+)-30 (99%). Thecoupling of dithiane 30 with R-(−)-glycidyl benzyl ether [(−)-31] thenafforded alcohol (−)-32 in 79% yield. Unmasking of the ketone moiety[(CF₃CO₂)₂IPh, 80%] and Evans stereocontrolled reduction (97%) providedthe anti diol (−)-34, which embodied all of the stereocenters infragment C.

Acid-catalyzed cyclization of (−)-34 (TsOH, room temperature) providedmethoxy pyran 35 in 87% yield as a 1:2 mixture of α and β anomers (FIG.8). Debenzylation (H₂, Pd/C) of 36 afforded alcohol 37 quantitatively.Exposure to EtSH and MgBr₂ in Et₂ O then gave a separable 6:1 mixture ofβ ethyl hemithioacetal (+)-38 and its α anomer in 83% yield. Swernoxidation of (+)-38 furnished the final fragment (+)-C in 86% yield.

Reaction of (−)-B with the organozinc derivative of (−)-A (FIG. 10) wasachieved by premixing iodide A with dried solid ZnCl₂ (ether, −78° C.)before addition of t-BuLi. It is believed that three equivalents oft-BuLi are required for complete consumption of (−)-A, probably becausethe first equivalent reacts with ZnCl₂. This modification increased theyield to 66% after flash chromatography.

Conversion of the Z trisubstituted olefin (−)-39 to the phosphoniumiodide (−)-49 began with selective removal of the PMB group, as in ourmodel study (DDQ, CH₂Cl₂, H₂O), furnishing (−)-40 in 87% yield (FIG.11). As shown in FIG. 12, alcohol (−)-40 furnished the requisite iodide42 almost exclusively, as indicated by NMR examination of the crudematerial. The very sensitive iodide was used without purification.Thorough mixing of iodide 42 with I-Pr₂NEt (3 equiv) followed byexposure to excess PPh₃ (15 equiv) without solvent at 80° C. generated(−)-49 in 37% yield for the two steps. The major by-product wascharacterized as (−)-50 (35% yield). The unsaturated model alcohol(+)-44 similarly afforded the Wittig salt (+)-46 in low yield (FIG. 13),whereas the saturated derivative (+)-51 gave phosphonium iodide (+)-53almost quantitatively.

Our preferred method to prepare compound 49 entails the mixing of iodide42 with I-Pr₂NEt (0.5 equiv.) and PPh₃ (4 equiv.) in benzene/toluene(7:3) and subjecting this mixture to an applied pressure of 10-15 Kbar.

As shown in FIG. 14, assembly of the discodermolide backbone entailedWittig coupling of aldehyde C with the ylide derived from AB phosphoniumsalt (−)-49 to install the C(8,9) Z alkene in (−)-54 (>49:1 Z/E, 76%yield). DIBAL reduction (88% yield) followed by oxidation of theresultant primary alcohol (−)-55 then produced aldehyde (−)-56 (96%).The terminal Z diene (−)-57 was elaborated via the Yamamoto protocol in70% yield with excellent selectivity (16:1 Z/E). After flashchromatography, hydrolysis of the hemithio acetal and mild DMSO/Ac₂Ooxidation provided lactone (−)-58 in 82% yield for the two steps.Removal of the PMB group (DDQ, CH₂Cl₂, H₂O, 95% yield) and carbamateformation (Cl₃CONCO, CH₂Cl₂, neutral Al₂O₃, 83%) afforded tris(TBSether) (−)-60. Final deprotection with 48% HF/CH₃CN (1:9) furnished (−)-discodermolide, identical with an authentic sample (FIG. 15).

Alternatively, lactone 58 can be prepared by the Wittig coupling ofaldehyde 67 with the ylide derived from 49, as shown in FIG. 42.Regioselective ring opening of benzylidene acetal 76 with DIBAL followedby oxidation with pyridinium dichromate affords aldehyde 77. Applicationof the Yamamoto olefination protocol affords compound 58. Alternatively,the diene installation can be effected using an alkyl chromium reagentgenerated by the procedure of Hodgson, et al., Tetrahedron Letters 1992,33, 4761. The aldehyde 67 can be prepared by from compound (−)-27(prepared generally according to the procedure of Smith, et al., J. Am.Chem. Soc. 1995, 117, 12011) by effecting a Mukaiyama aldol reactionbetween aldehyde 27 and enol ether 63 to form enone 64. Reduction ofenone 64 furnished a 9:1 mixture of carbinols, favoring the desiredisomer. Protection of the newly formed carbinol with TBSCl andsubsequent ozonolysis of the trisubstituted olefin provides 67 inapproximately 80% overall yield, as shown in FIG. 38.

Alternatively, the discodermolide backbone can be synthesized byinstalling the terminal diene before Wittig coupling with Fragment C. Asshown in FIG. 40, regioselective ring opening of benzylidine acetal 39with DIBAL-H followed by oxidation and application of the Yamamotoolefination protocol provides diene 73. Selective removal of the lesshindered PMB using DDQ/H₂O is followed by conversion to the primaryiodide and phosphonium salt 75. Alternatively, the primary PMB can beenhanced for either a dimethoxy benzyl ether or silyl protecting groupearlier in the sequence. Application of Dauben's high pressureconditions results in approximately 75% yield of the desired phosphoniumsalt. Further assembly of the discodermolide backbone entails Wittigcoupling of aldehyde 67 with the ylide derived from phosphonium salt 75to afford 58. Further manipulation as indicated above (FIG. 15) provides(+)-discodermolide.

Another preferred route to phosphonium salt 75 is depicted in FIGS. 43and 44. Starting from alcohol 40, trityl ether 87 may be prepared bycontacting with trityl chloride andN,N-dimethyl-pyridine (DMAP) in hotpyridine (FIG. 43). Reductive opening of the anisylidine acetalfunctionality of 87 with DIBALH provides the primary alcohol 88.Oxidation of 88 with Dess-Martin Periodane (DMP) followed by Yamamotoolefination provides diene 90 with approximately a 8-11:1diastereoselectivity.

The trityl protecting group of 90 is preferably removed utilizing amodified Boeckman protocol, as described, for example, in Boeckman, R.K., Jr.; Potenza, J. C. Tetrahedron Lett. 1985, 26, 1411, the disclosureof which is hereby incorporated by reference in its entirety, to providealcohol 74. (FIG. 44). Wittig salt 75 may be prepared via conversion ofalcohol 74 to the corresponding iodide employing a modified Coreyprotocol (PPh₃, I2, PhH/Et2O) and subjection of the unstable iodide toexcess PPh₃ at high pressure (12.8 Kbar) in a buffered, non-polar medium(Hunig's base, toluene/benzene).

Treatment of tetraene 58 (a mixture of diene isomers; ca 8-12:1) withDDQ results in oxidative removal of the PMB ether and, selectivedestruction of the trans-diene impurity preferably yieldsdiastereomerically pure alcohol 59 after flash chromatography (FIG. 45).

Alcohol 59 may be subjected to the Kocovsky protocol to yield thecarbamate 60 (Scheme 46). Carbamate 60 is preferably taken onto thenatural product (+)-discodermolide by slow addition of acid, forexample, 3N HCl to a methanol solution of 60 over a suitable time periodsuch as 12 hours. Discodermolide may be purified by flash chromatographyfollowed by crystallization from, for example, neat acetonitrle.

An Aldol reaction between aldehyde 92 and the corresponding enolate ofamide 93 yields the common precursor 5 in three steps (FIG. 47). Amide93 can be easily prepared from the commercially available acid chloride94 (FIG. 48).

Alternative synthetic routes to tetraene 58 are depicted in FIGS. 49 and50. A palladium catalyzed coupling between vinyl iodide 96 andorganozinc 97 yields 58 (FIG. 49). Alternatively 58 can be constructedvia the coupling of 98 with aldehyde 67 (FIG. 50).

Alkyl groups according to the invention include but are not limited tostraight chain and branched chain hydrocarbons such as methyl, ethyl,propyl, pentyl, isopropyl, 2-butyl, isobutyl, 2-methylbutyl, andisopentyl moieties having 1 to about 10 carbon atoms, preferably 1 toabout 6 carbon atoms. Cycloalkyl groups are cyclic hydrocarbons having 3to about 10 carbon atoms such as cyclopentyl and cyclohexyl groups.Heterocycloalkyl groups are cycloalkyl groups which include at least oneheteroatom (i.e., an atom which is not carbon, such as O, S, or N) intheir cyclic backbone. Alkenyl groups according to the invention arestraight chain or branched chain hydrocarbons that include one or morecarbon-carbon double bonds. Preferred alkenyl groups are those having 2to about 10 carbon atoms. Alkyl, cycloalkyl, heterocycloalkyl, andalkenyl groups according to the invention optionally can beunsubstituted or can bear one or more substituents such as, for example,halogen hydroxyl, amine, and epoxy groups.

Aryl groups according to the invention are aromatic and heteroaromaticgroups having 6 to about 14 carbon atoms, preferably from 6 to about 10carbon atoms, including, for example, naphthyl, phenyl, indolyl, andxylyl groups and substituted derivatives thereof, particularly thosesubstituted with amino, nitro, hydroxy, methyl, methoxy, thiomethyl,trifluoromethyl, mercaptyl, and carboxy groups. Alkaryl groups aregroups that contain alkyl and aryl portions and are covalently bound toother groups through the alkyl portion, as in a benzyl group.Alkheteroaryl groups are groups that contain alkyl and heteroarylportions and are covalently bound to other groups through the alkylportion.

The target compounds and intermediates of the present invention maycontain protecting groups. Protecting groups are known per se aschemical functional groups that can be selectively appended to andremoved from functionality, such as hydroxyl and amine groups, presentin a chemical compound to render such functionality inert to certainchemical reaction conditions to which the compound is exposed. See,e.g., Greene and Wuts, Protective Groups in Organic Synthesis, 2dedition, John Wiley & Sons, New York, 1991. Numerous hydroxyl protectinggroups are known in the art, including the acid-labilet-butyldimethylsilyl, diethylisopropylsilyl, and triethylsilyl groupsand the acid-stable aralkyl (e.g., benzyl), triisopropylsilyl, andt-butyldiphenylsilyl groups. Useful amine protecting groups include theallyloxycarbonyl (Alloc), benzyloxycarbonyl (CBz),chlorobenzyloxycarbonyl, t-butyloxycarbonyl (Boc),fluorenylmethoxycarbonyl (Fmoc), isonicotinyloxycarbonyl (I-Noc) groups.

As used herein, the term “oxidatively labile group” is intended toinclude all groups known to be removed by an oxidizing agent. An exampleof an oxidizing agent includes, but is not limited to,2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).

The term amino acid as used herein is intended to include allnaturally-occurring and synthetic amino acids known in the art. Ingeneral, amino acids have structure H₂N-CH(R_(c))—C(O)OH where R_(c) isthe amino acid side chain. Representative, naturally-occurring sidechains are shown in Table 1. TABLE 1 CH₃— CH₃—CH₂—S—CH₂—CH₂— HO—CH₂—HO—CH₂—CH₂— C₆H₅—CH₂— CH₃—CH₂(OH)— HO—C₆H₅—CH₂— HO₂C—CH₂—NH₂C(O)—CH₂—

HCO₂—CH₂—CH₂—NH₂C(O)—CH₂—CH₂—(CH₃)₂—CH—(CH₃)₂—CH—CH₂—CH₃—CH₂—CH₂—

H₂N—CH₂—CH₂—CH₂—H₂N—C(NH)—NH—CH₂—CH₂—CH₂—H₂N—C(O)—NH—CH₂—CH₂—CH₂—CH₃—CH₂—CH(CH₃)—HS—CH₂— CH₃—CH₂—CH₂—CH₂— HO₂C—CH(NH₂)—CH₂—S— H₂N—CH₂—CH₂—CH₂—CH₂— S—CH₂—CH₃—CH₂— CH₃—S—CH₂—CH₂—Hydrophobic amino acid side chains are preferred, including the CH₃—,C₆H₅—CH₂—, CH₃—CH₂—, CH₃—S—CH₂—CH₂—, (CH₃)₂—CH—, (CH₃)₂—CH—CH₂—,CH₃—CH₂—CH(CH₃)—, and CH₃—CH₂—CH₂—CH₂— side chains. Peptides accordingto the invention are linear, branched, or cyclic chemical structurescontaining at least 2 covalently bound amino acids.

Certain compounds of the invention contain amino groups and, therefore,are capable of forming salts with various inorganic and organic acids.Such salts are also within the scope of this invention. Representativesalts include acetate, adipate, benzoate, benzenesulfonate, bisulfate,butyrate, citrate, camphorate, camphorsulfonate, ethanesulfonate,fumarate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, methanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalenesulfonate, nitrate, oxalate, pamoate,persulfate, picrate, pivalate, propionate, succinate, sulfate, tartrate,tosylate, and undecanoate. The salts can be formed by conventionalmeans, such as by reacting the free base form of the product with one ormore equivalents of the appropriate acid in a solvent or medium in whichthe salt is insoluble, or in a solvent such as water which is laterremoved in vacuo or by freeze drying. The salts also can be formed byexchanging the anions of an existing salt for another anion on asuitable ion exchange resin.

All processes described herein are contemplated to be run on any scale,including milligram, gram, kilogram, and commercial scale. Preferredprocesses according to the invention include contacting a phosphoniumsalt of formula I with base and an alkylthiol of formula II:

to form a diene of formula III:

wherein:

-   -   R₁, R₂, R₃, R₇, R₈, R₁₁, R₁₂ and R₁₃ are, independently, C₁-C₁₀        alkyl;    -   X is a halogen;    -   R₆ is selected from the group consisting of H and C₁-C₁₀ alkyl;    -   Z, Z₁, and Z₂ are, independently, O, S or NR′;    -   R₄, R₉, R₁₄, and R₁₅ are, independently, acid labile hydroxyl        protecting groups;    -   R₅ is C₆-C₁₄ aryl;    -   Y is O, S or NR′;    -   R′ and R₁₆ are, independently, hydrogen or C₁-C₆ alkyl; and    -   R₁₈ is C₆-C₁₄ aryl.

Such procedures preferably are run in solvents such as tetrahydrofuranat −78° C.-0° C. Suitable bases for such procedures include sodiumhexamethyldisilazide, potassium hexamethyldisilazide, and n-butyllithiumwith hexamethyl-phosphoramide.

Phosphonium salts of formula I can be prepared by reacting acorresponding halogen of formula XXXXVI:

with P(R₁₈)₃ in an for a time and under conditions effective to producethe salt. This reaction preferably is conducted in a aromatichydrocarbon organic solvent such as toluene or benzene. A mixture ofbenzene and toluene in a ratio of 7:3 is preferred at a pressure ofabout 5 Kbar to about 20 Kbar.

The methods of the invention involve also are directed to the synthesisof alkenes of formula IV:

by contacting organometallic reagents of formula Va:

with vinyl halides of formula VIa:

wherein M is Li, Cu, Mg, or Zn, and R₁₀ is an acid stable hydroxylprotecting group. Alternatively, a vinyl halide of formula Vb:

is contacted with an organometallic compound of formula VIb:

Such reactions preferably are performed in the presence of apalladium-containing catalyst such as Pd(PPh₃)₄, Pd(Cl₂) (PPh₃)₂,Pd(Cl₂) (dppf)₂.

In yet another aspect, the synthetic methods of the invention aredirected to the preparation of compounds having formula VII:

by contacting a diene of formula VIIIa:

with an organometallic compound having formula Va wherein R₂₄ ishydrogen and R₂₅ is hydrogen or an acid stable hydroxyl protectinggroup. Alternatively, an organometallic compound having formula VIIIb iscontacted with a vinyl halide having formula Vb.

The reaction of compounds having formulas V and VIII preferably isperformed in ether in the presence of a palladium- or nickel-containingcatalyst.

The methods of the invention also involve producing dienes havingformula VIIIa by contacting phosphonium salts having formula IX:

with a base such as sodium hexamethyl disilazide and an alkylthiolcompound having formula II. Such procedures preferably are run insolvents such as tetrahydrofuran at −78° C.-0° C. Suitable bases forsuch procedures include sodium hexamethyldisilazide, potassiumhexamethyldisilazide, and n-butyllithium with hexamethylphosphoramide.

The methods of the invention also involve producing compounds of formulaXXIII:

by contacting an aldehyde of formula XXIV:

with an enol ether of formula XXV:

in the presence of a titanium salt and an organic acid to form an enoneof formula XXVI:

Preferably, the reaction between aldehyde 27 and the enol ether 62 is aMukaiyama aldol reaction wherein the Lewis acid is a titanium salt (suchas TiCl₄) or some other Ti(IV) of Sn(IV) Lewis acid (such as SnCl₄) andthe organic acid is trichloroacetic acid, trifluoroacetic acid, sulfuricacid, or pyridinium p-toluenesulfonate. Following the aldol reaction,enone 64 is contacted with a reducing agent to form the correspondingenol 65. Preferably, the reducing agent is potassiumtri-sec-butylborohydride or sodium tri-sec-butylborohydride(commercially available in THF as K-Selectride® and N-Selectride®,respectively) but may include chiral reducing agents such as lithiumB-isopinocampheyl-9-borabicyclo[3.3.1]nonyl hydride (commerciallyavailable in THF as Alpine-Hydride®.

According to the present invention, enol 65 is then contacted with acompound having formula R-L wherein R is an acid labile protecting groupand L is a leaving group. Preferably, R-L is t-butyldimethylsilylchloride or t-butyldimethysilyl triflate.

The protected enol is then oxidized with an oxidizing agent such as O₃or the reagent combination of NaIO₄ with catalytic OsO₄ for a time andunder conditions effective to oxidize the carbon-carbon double bond ofthe protected enol.

The methods of the present invention are also directed to the synthesisof diene having formula XXXIII:

by contacting phosphonium salts of formula XXXIV:

with base and a compound of formula XXXV:

Suitable bases for such procedures include potassiumhexamethyldisilazide, sodium hexamethyldisilazide, n

butyllithium and potassium t-butoxide. A preferred solvent is toluene,preferably at a temperature of −78° C.-0° C.

Phosphonium salts of formula XXXIV can be prepared by reacting acorresponding halogen of formula XXXXVII:

with P(R₁₈)₃ in an for a time and under conditions effective to producethe salt. This reaction preferably is conducted in a aromatichydrocarbon organic solvent such as toluene or benzene. A mixture ofbenzene and toluene in a ratio of 7:3 is preferred at a pressure ofabout 5 Kbar to about 20 Kbar.

Further processes of the invention involve producing compound havingformula XXXVI:

by contacting a compound of formula XXXVII:

with base and a phosphonium salt of formula XXXIV:

Preferred bases include sodium hexamethyldisilazide, potassiumhexamethyldisilazide, n-butyllithium with hexamethyl-phosphoramide, andpotassium t-butoxide. A preferred solvent is toluene, preferably at atemperature of −78° C.-0° C.

According to methods of the invention, removal of the acid stableprotective group and carbamate formation followed by final deprotectionfurnishes compounds having formula:

Although preferred synthetic methods are those directed to (+)-discodermolide and compounds having like stereochemistry, those skilledin the art will recognize that the methods disclosed herein can bereadily adapted to the synthesis of antipodal compounds such as, forexample, (−)-discodermolide, and vice versa. All such synthetic methodsare within the scope of the present invention.

The present invention provides compounds which mimic the chemical and/orbiological activity of the discodermolides. In preferred embodiments,such compounds have formula XI:

where

-   -   R₃₀ is substituted or unsubstituted C₁-C₁₀ alkyl or a moiety        formula XII or XIII:        where A is C₁-C₂₀ alkyl, —CH₂NH(T) or a moiety of formula XIV:        wherein    -   T is peptide having 1 to about 10 amino acids;    -   R₃₂, R₄₀, R₄₂, R₄₃, R₄₆, R₄₇, and R₄₈ are, independently,        hydrogen or C₁-C₆ alkyl;    -   R₄₁ is a side chain of an amino acid;    -   W₁ and W₂ are, independently, —OR₄₉ or —NHP₁;    -   P₁ is hydrogen or an amine protecting group;    -   R₃₃ and R₃₆ are, independently, hydrogen, C₁-C₁₀ alkyl, —OR₅₀,        ═O or together form —CH₂—CH₂—;    -   R₃₄ and R₃₅ are, independently, hydrogen or together form        —C(H)═C(H)—C(H)═C(H)—;    -   R₃₉ is —OR₅₁ or —CH₂—R₅₁;    -   R₃₁ and R₄₄ are, independently, C₁-C₁₀ alkyl;    -   Q₁ and Q₂ are, independently, hydrogen, —OR_(Q), —NHR₅₂,        —OC(═O)NH₂ or together form —O—C(O)—NH—;    -   R_(Q) is hydrogen or a hydroxyl protecting group;    -   R₅₁ is substituted or unsubstituted C₆-C₁₄ aryl,        tetrahydropyranyl, furanosyl, pyranosyl, C₃-C₁₀ lactonyl or        2-pyranonyl;    -   R₄₅ is C₁-C₆ alkenyl, C₁-C₆ alkyl, C₆-C₁₄ aryl, C₂-C₁₀        heterocycloalkyl, C₃-C₁₀ cycloalkyl, or C₇-C₁₅ aralkyl; and    -   R₄₉, R₅₀, and R₅₂ are, independently, hydrogen or C₁-C₆ alkyl.

Some preferred compounds having formula XI are shown in FIGS. 33-36.

In other aspects, the present invention provides a process for forming ahalogenated olefin of formula:

wherein:

-   -   R₆ is selected from H and C₁-C₆ alkyl;    -   R₇ and R₈ are independently C₁-C₁₀ alkyl;    -   R₉ is an acid labile hydroxyl protecting group;    -   R₁₀ is an oxidatively labile protecting group; and,    -   X is halogen;        the process comprising contacting an aldehyde of formula:        with a compound of formula (R₁₈)₃ PCHXR₆ in the presence of        base, wherein R₁₈ is C₆-C₁₄ aryl, for a time and conditions        effective to form the halogenated olefin.

Preferred conditions include cooling a suspension of R₆Ph₃PX in anaprotic solvent, such as tetrahydrofuran, at about 0° C. to −25° C., andcontacting the suspension with a strong base such as an alkyl metal.Suitable strong bases include, but are not limited to alkyl lithiums,such as butyl lithium, t-butyl lithium, and the like. The solution maybe added to a precooled solution of X₂, preferably at a rate such thatthe temperature of the resultant solution does not exceed −70° C. Anadditional base, such as sodium hexamethyl disilazide, is preferablyadded over approximately a 10 to 60 minute period followed byintroduction of the aldehyde.

In certain preferred embodiments, R₆, R₇, and R₈ are independently C₁-C₄alkyl, and R₁₈ is phenyl. In certain more preferred embodiments, R₆, R₇,and R₈ are methyl, X is iodine, R₂ is tert-butyldimethylsilyl, and R₁₀is paramethoxybenzyl.

The present invention also provides process for forming a triene offormula:

wherein:

-   -   R₁, R₂, R₇, and R₈ are independently C₁-C₁₀ alkyl;    -   R₃and R₆ are independently selected from hydrogen and C₁-C₆        alkyl;    -   R₄ and R₉ are independently acid labile hydroxyl protecting        groups;    -   R₂₅ is an oxidatively labile hydroxyl protecting group; and;    -   R₁₀ is a hydroxy protecting group;        the process comprising contacting an aldehyde of formula:        with a compound of formula Ph₂PCH₂CH═CH₂ in the presence of a        base and a compound of formula Ti(O—R₂₇)₄, wherein R₂₇ is C₁₋₆        alkyl; followed by treatment with R₂₈X wherein R₂₈ is C₁₋₆ alkyl        and X is a halogen, for a time and under conditions effective to        form the triene.

Preferable conditions include precooling a solution of Ph₂PCH₂CH═CH₂ inan aprotic solvent, such as tetrahydrofuran, to a temperature of below0° C., more preferably below −70° C., followed by the addition over asuitable time period of a strong base such as an alkyl metal. Strongbases may include, but are not limited to alkyl lithiums, such as butyllithium, t-butyl lithium, and the like. The solution is preferablytreated with Ti(O—R₂₇)₄ and stirred for a suitable period, followed bythe introduction of the aldehyde. An excess of R₂₈X is then added andthe solution warmed over a suitable time period to afford the triene.

In certain preferred embodiments, R₁, R₂, R₇, and R₈ are independentlyC₁-C₄ alkyl; R₁₀ is selected from triphenyl methyl, dimethoxyl benzyl,and dimethoxybenzyl-O-methyl; the base is C₁-C₆ alkyl lithium; R₂₇ isisopropyl, R₂₈ is methyl; and X is iodine.

In another embodiment, the process for forming the triene furthercomprising contacting the triene with a borane compound of formula:

wherein X is a first halogen and R₂₆ is selected from C₆₋₁₄ aryl andC₁₋₆ alkyl, to form a triene alcohol of formula:

and;

-   -   contacting the triene alcohol with a halogen such as iodine in        the presence of base and P(R₁₈)₃ to form the corresponding        iodide, followed by further treatment of the resulting iodide        with Hunig's base and P(R₁₈)₃ under conditions to form a        phosphonium salt of formula:

Preferable conditions include adding a protic solvent to a solution ofthe borane and a polar solvent. Preferable protic solvent include, butare not limited to, alcoholic solvents such as methanol. Preferablepolar solvents include, but are not limited to, chlorinated solvents.The solution may be added over a suitable period of time to a solutionof trityl ether to provide the triene alcohol. The triene alcohol ispreferably stirred in a solution of P(R₁₈)₃ and a base, to which Y₂ isadded. In certain embodiments, R₁₈ is phenyl, the base is imidazole andY₂ is iodine. The resultant compound is preferably stirred in a solutionto which an amine base, such as Hunig's base, is added followed byP(R₁₈)₃. The resultant solution may be subjected to elevated pressurefor a period of time sufficient to form the phosphonium salt.

In certain embodiments, the aldehyde of formula:

is formed by a process comprising contacting a compound of formula:

wherein:

-   -   R₁, R₂, R₇, and R₈ are independently C₁-C₁₀ alkyl;    -   R₃ and R₆ are independently selected from hydrogen and C₁-C₆        alkyl;    -   R₄ and R₉ are independently acid labile hydroxyl protecting        groups; and    -   R₁₀ is a trityl group;        with hydride to form an alcohol of formula:        and oxidizing the alcohol to form the aldehyde.

The formation of the alcohol as well as the oxidation may be performed,for example, at reduced temperatures such as about O° C. or lower. Incertain embodiments, the hydride is diisobutylaluminum hydride (DIBAL-H)and the oxidation is accomplished through treatment of the alcohol withDess-Martin periodinane.

The present invention further provides a process for forming a tetraeneof formula:

wherein:

-   -   R₁, R₂, R₇, and R₈ are independently C₁-C₁₀ alkyl;    -   R₃, R₆, and R₁₆ are independently selected from hydrogen and        C₁-C₆ alkyl;    -   R₄ and R₉ are independently an acid labile hydroxyl protecting        group;    -   R₂₅ is an acid stable hydroxyl protecting group; and    -   J is selected from:        alkaryl, and alkheteroaryl;        wherein R₃₂ is H or C₁-C₆ alkyl and R₃₃ is H or an acid labile        hydroxyl protecting group;        the process comprising contacting a compound of the formula:        J-CHO        with a phosphonium salt of the formula:        wherein R₁₈ is C₆-C₁₄ aryl, in the presence of a base for a time        and under conditions effective to form the tetraene. In certain        preferred embodiments, the process according to claim 11 wherein        R₁, R₂, R₇, and R₈ are independently C₁-C₄ alkyl, R₃ and R₆ are        independently selected from hydrogen and C₁-C₄ alkyl, and R₃₂ is        C₁₋₄ alkyl.

The present invention also provides a process for forming a tetraene offormula:

wherein:

-   -   R₁, R₂, R₇, and R₈ are independently C₁-C₁₀ alkyl;    -   R₃, R₆, and R₁₆ are independently selected from hydrogen and        C₁-C₆ alkyl; and    -   J is selected from:        alkaryl, and alkheteroaryl;        wherein R₃₂ is H or C₁-C₆ alkyl and R₃₃ is H;        the process comprising contacting an alcohol of formula:        wherein R₄, R₉, and R₃₃ are acid labile hydroxyl protecting        groups, with an isocyanate of the formula:        X₃CC (═O)NCO        wherein X is a halogen, to form a carbamate intermediate;        contacting the carbamate intermediate with neutral alumina to        form a carbamate of formula:        and;        removing the acid labile hydroxyl protecting groups by        contacting the carbamate with acid in a protic solvent to form        the tetraene.

A solution of the alcohol in a polar solvent may be contacted with theisocyanate at room temperature for a period of about 15 to 45 minutesfollowed by loading the solution directly onto neutral alumina. After asuitable period of time, for example, several hours, the material may beflushed from the column with an suitable solvent system. In certainpreferred embodiments, the acid labile protecting group is removed withaqueous hydrochloric acid in an alcoholic solvent. More preferably, theaddition of acid is performed in portions and over a period of timewhich minimizes precipitation.

In certain preferred embodiments, the alcohol is formed by contacting acompound of formula:

with a compound of formula:

wherein R₂₅ is an oxidatively labile protecting hydroxyl protectinggroup, and R₃₅ is selected from C₁-C₄ alkyl and a halogen, in thepresence of a metal coupling catalyst for a time and under conditionseffective to form a coupling product of formula:

and deprotecting the coupling product to form the alcohol. In certainpreferred embodiments, R₁, R₂, R₇, and R₈ are independently C₁-C₄ alkyl,R₃, R₆, and R₁₆ are independently hydrogen or C₁-C₄ alkyl, J is:

the isocyanate is Cl₃CC(═O)NCO, the acid is HCl and the polar solvent isan alcohol selected from methanol, ethanol, and isopropanol. In otherpreferred embodiments, the alcohol is formed by contacting a compound offormula:

wherein:

-   -   R₂₅ is an oxidatively labile protecting group;    -   R₃₅ is selected from CH₂P(═O)Ph₂ and    -   X is a halogen; and    -   R₁₈ is C₆₋₁₄ aryl;        with a compound of formula: J-C(O)R¹⁶;        in the presence of a base to form a coupling product of formula:        and deprotecting the coupling product (removing R₂₅) to form the        alcohol. In certain more preferred embodiments, the protic        solvent is an alcohol selected from methanol, ethanol, and        isopropanol.

In other embodiments, the present invention provides a process forforming an alcohol of formula:

wherein:

-   -   R₇ and R₈ are independently C₁-C₁₀ alkyl;    -   R₁₀ is an acid stable hydroxyl protecting group;    -   R₃₄ is selected from (CH₂)_(n)C₆-C₁₄ aryl and (CH₂OCH₂)C₆-C₁₄        aryl, wherein the aryl is substituted with 0-3 R₃₅;    -   R₃₅ is selected from F, CF₃, Br, Cl, and NO₂; and    -   n is selected from 0 and 1;        the process comprising contacting a compound of formula:        with the enolate of a compound of formula:        in the presence of Lewis acid for a time and under conditions        effective to form the alcohol.

The present invention also provides a compound of formula:

wherein:

-   -   R₆ is C₁-C₄ alkyl;    -   R₇ and R₈ are independently C₁-C₁₀ alkyl;    -   R₉ is an acid labile hydroxyl protecting group;    -   R₁₀ is an acid stable hydroxyl protecting group; and    -   X is halogen.

The present invention also provides a compound of formula:

wherein:

-   -   R₁, R₂, R₇, and R₈ are independently C₁-C₁₀ alkyl;    -   R₃ and R₆ are independently selected from hydrogen and C₁-C₆        alkyl;    -   R₄ and R₉ are independently acid labile hydroxyl protecting        groups;    -   R₂₅ is an oxidatively labile hydroxyl protecting group; and    -   R₁₀ is a trityl group; and    -   R₂₉ is selected from OH, CHO, and —CH═CH—CH═CH₂.        In certain preferred compounds, R₁, R₂, R₇, and R₈ are methyl,        and R₃ and R₆ are independently selected from hydrogen and        methyl.

In other embodiments, the present invention provides a compound offormula:

wherein:

-   -   R₁, R₂, R₇, and R₈ are independently C₁-C₁₀ alkyl;    -   R₃, R₆, and R₁₆ are independently selected from hydrogen and        C₁-C₆ alkyl;    -   R₄, R₉, and R₁₄ are acid labile hydroxyl protecting groups;    -   R₄₀ is selected from OR₂₅ and OC(═O)NH₂;    -   R₂₅ is an acid stable protecting group; and    -   J is selectedfrom:        wherein R₃₂ is C₁-C₆ alkyl, R₃₃ is selected from H and an acid        labile hydroxy protecting group, and R₃₄ is C₁-C₆ alkyl.

The present invention also provides a compound of formula:

wherein:

-   -   R₁, R₂, R₇, and R₈ are independently selected from hydrogen and        C₁-C₁₀ alkyl;    -   R₃, R₆, and R₁₆ are independently selected from hydrogen and        C₁-C₆ alkyl;    -   R₄ and R₉ are selected from hydrogen and acid labile hydroxyl        protecting groups;    -   R₄₀ is selected from OR₂₅ and OC(═O)NH₂;    -   R₂₅ is selected from hydrogen and an oxidatively labile        protecting group; and    -   J is selected from:    -   alkaryl and alkheteroaryl wherein aryl and heteroaryl are        optionally substituted and alk is optionally substituted with        R₃₂ or OR₃₃;        wherein:    -   R₃₂ is selected from hydrogen and C₁-C₆ alkyl; and    -   R₃₃ is selected from hydrogen and an acid labile hydroxy        protecting group. In certain embodiments, R⁶ is H.

In certain preferred embodiments, R₆ is H, R₁, R₂, R₇, and R₈ aremethyl, R₄, R₉ and R₃₃ are hydrogen. In other preferred embodiments, thecompound of claim 1 wherein R₁, R₂, R₇, and R₈ are methyl; R₄, R₆, andR₉ are hydrogen; and R₄₀ is —OC(O)NH₂. In other preferred embodiments, Jis

wherein R₃₂ is methyl and R₃₃ is hydrogen.

In other preferred embodiments, R₁, R₂, R₆, R₇,and R₈ are methyl; R₄ andR₉ are H; R₄₀ is —OC(O)NH₂; and J is

wherein R₃₂ is methyl and R₃₃ is H.

In other preferred embodiments, J is

wherein the phenyl group is optionally substituted with C₁-C₄ alkyl,haloalkyl, hydroxy, alkoxy, or haloalkoxy. In other preferredembodiments, the phenyl is substituted with OH.

In certain preferred embodiments, the present invention provides acompound having the following formula:

wherein:

-   -   R₁, R₂, R₇, and R₈ are independently hydrogen or C₁-C₁₀ alkyl;    -   R₃, R₆, and R₁₆ are independently hydrogen or C₁-C₆ alkyl;    -   R₄, and R₉ are independently hydrogen or acid labile hydroxyl        protecting groups;    -   R₄₀ is selected from OR₂₅ and OC(═O)NH₂;    -   R₂₅ is hydrogen or an oxidatively labile protecting group;        and J is selected from:    -   alkaryl and alkheteroaryl wherein aryl and heteroaryl are        optionally substituted and alk is optionally substituted with        R₃₂ or OR₃₃;        wherein    -   R₃₂ is hydrogen or C₁-C₆ alkyl; and    -   R₃₃ is hydrogen or an acid labile hydroxy protecting group. In        certain preferred embodiments, R₆ is H. In other embodiments,        R₁, R₂, R₇, and R₈ are methyl. In other embodiments, R₄, R₉, and        R₃₃ are hydrogen. In other embodiments, R₁, R₂, R₇, and R₈ are        methyl; R₄, R₆, R₉, and R₃₃ are H; and R₄₀ is —OC(O)NH₂.

In certain embodiments, the present invention provides a compoundshaving the formula:

wherein

-   -   R₂, R₇, and R₈ are independently hydrogen or C₁-C₁₀ alkyl;    -   R₃, R₆, and R₁₆ are independently hydrogen or C₁-C₆ alkyl;    -   R₄, R₉, and R₃₃ are independently hydrogen or acid labile        hydroxyl protecting groups;    -   R₄₀ is selected from OR₂₅ and OC(═O)NH₂;    -   R₂₅ is hydrogen or an oxidatively labile protecting group;        and    -   J is selected from:        alkaryl and alkheteroaryl wherein aryl and heteroaryl are        optionally substituted and alk is optionally substituted with        R₃₂ or OR₃₃;        wherein    -   R₃₂ is hydrogen or C₁-C₆ alkyl; and    -   R₃₃ is hydrogen or an acid labile hydroxy protecting group.

In certain preferred embodiments, R₆ is H. In other embodiments, R₁, R₂,R₇, and R₈ are methyl.

In certain embodiments, the present invention provides a compound havingthe formula:

wherein:

-   -   R₁, R₂, R₇, and R₈ are independently hydrogen or C₁-C₁₀ alkyl;    -   R₃, R₆, and R₁₆ are independently hydrogen or C₁-C₆ alkyl;    -   R₄, R₉, and R₃₃ are independently hydrogen or acid labile        hydroxyl protecting groups;    -   R₂₅ is hydrogen or an oxidatively labile protecting group;    -   R₄₀ is selected from OR₂₅ and OC(═O)NH₂;    -   R′ is methyl or alkyl-R″; and    -   R″ is C₁-C₁₀ alkoxy, hydroxy, or —C(O)CH₃.

In certain preferred embodiments, R₆ is hydrogen. In other embodiments,R₁, R₂, R₇, and R₈ are methyl. In other embodiments, R₄, R₉, and R₃₃ areH. In other embodiments, R₁, R₂, R₇, and R₈ are methyl; R₄, R₆, R₉, andR₃₃ are H; and R₄₀ is —OC(O)NH₂.

The compounds of the present invention can be admixed with carriers,excipients, and/or diluents to form novel compositions. Suchcompositions can be used in prophylactic, diagnostic, and/or therapeutictechniques. By administering an effective amount of such a composition,prophylactic or therapeutic responses can be produced in a human or someother type mammal. It will be appreciated that the production ofprophylactic or therapeutic responses includes the initiation orenhancement of desirable responses, as well as the mitigation,cessation, or suppression of undesirable responses. The compositions ofthe invention are expected to find use, for example, in the inhibitionof undesired cell proliferation (e.g., cancer) and in the inhibition ofrejection in organ transplantation procedures. (See, e.g., Longley, etal., Transplantation 1991, 52, 650 and 656).

Compositions of the invention can be prepared by any of the methods wellknown in the pharmaceutical art, for example, as described inRemington's Pharmaceutical Sciences (Mack Pub. Co., Easton, Pa., 1980).The compositions can include a compound of the invention as an activeingredient in admixture with an organic or inorganic carrier orexcipient suitable, for example, for oral administration. Other suitablemodes of administration will be apparent to those skilled in the art.The compound of the invention can be compounded, for example, with theusual non-toxic, pharmaceutically acceptable carriers for tablets,pellets, capsules, solutions, suppositories, suspensions, and any otherform suitable for use. The carriers which can be used are water,glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesiumtrisilicate, talc, corn starch, keratin, colloidal silica, potatostarch, urea and other carriers suitable for use in manufacturingpreparations, in solid, semisolid, or liquid form, and in additionauxiliary, stabilizing, thickening and coloring agents and perfumes maybe used. The compound of the invention is included in the pharmaceuticalcomposition in an amount sufficient to produce the desired effect uponthe process or condition of diseases.

For oral administration, tablets containing various excipients such asmicrocrystalline cellulose, sodium citrate, calcium carbonate, dicalciumphosphate and glycine may be employed along with various disintegrantssuch as starch and preferably corn, potato or tapioca starch, alginicacid and certain complex silicates, together with granulation binderslike polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,lubricating agents such as magnesium stearate, sodium lauryl sulfate andtalc are often very useful for tableting purposes. Solid compositions ofa similar type may also be employed as fillers in appropriately soluble(e.g., gelatin) capsules; preferred materials in this connection alsoinclude lactose or milk sugar as well as high molecular weightpolyethylene glycols.

When aqueous suspensions and/or elixirs are desired for oraladministration, the active ingredient may be combined with varioussweetening or flavoring agents, coloring matter or dyes, and, if sodesired, emulsifying and/or suspending agents as well, together withsuch diluents as water, ethanol, glycerin and various like combinationsthereof.

For parenteral administration, suspensions containing a compound of theinvention in, for example, aqueous propylene glycol can be employed. Thesuspensions should be suitably buffered (preferably pH>8) if necessaryand the liquid diluent first rendered isotonic. The aqueous suspensionsare suitable for intravenous injection purposes. The preparation of suchsuspensions under sterile conditions is readily accomplished by standardpharmaceutical techniques well-known to those skilled in the art.Additionally, it is possible to administer the compounds of theinvention topically and this may preferably be done by way of creams,jellies, gels, pastes, ointments and the like, in accordance withstandard pharmaceutical practice.

The compounds of the invention can be employed as the sole active agentin a pharmaceutical composition or can be used in combination with otheractive ingredients, e.g., other agents useful in diseases or disorders.

The amount of active ingredient that is to be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. The specificdose level for any particular patient will depend on a variety offactors including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,route of administration, rate of excretion, drug combination, and theseverity of the particular disease undergoing therapy. In someinstances, dosage levels below the lower limit of the aforesaid rangemay be more than adequate, while in other cases still larger doses maybe employed without causing any harmful side effects provided that suchhigher dose levels are first divided into several small doses foradministration throughout the day. The concentrations of the activeingredient in therapeutic compositions will vary depending upon a numberof factors, including the dosage of the drug to be administered, thechemical characteristics (e.g., hydrophobicity) of the activeingredient, and the route of administration. Typical dose ranges arefrom about 285 μg/kg of body weight per day in three divided doses; apreferred dose range is from about 42 μg/kg to about 171 μg/kg of bodyweight per day. The preferred dosage to be administered is likely todepend on such variables as the type and extent of progression of thedisease or disorder, the overall health status of the particularpatient, the relative biological efficacy of the compound selected, andformulation of the compound excipient, and its route of administration,as well as other factors, including bioavailability, which is in turninfluenced by several factors well known to those skilled in the art.

Additional objects, advantages, and novel features of this inventionwill become apparent to those skilled in the art upon examination of thefollowing examples thereof, which are not intended to be limiting.

All reactions were carried out in oven-dried or flame-dried glasswareunder an argon atmosphere, unless otherwise noted. All solvents werereagent grade. Diethyl ether and tetrahydrofuran (THF) were freshlydistilled from sodium/benzophenone under argon before use.Dichloromethane, benzene and diisopropyl amine were freshly distilledfrom calcium hydride before use. Triethylamine and diisopropylethylaminewere distilled from calcium hydride and stored over potassium hydroxide.Hexamethylphosphoramide was freshly distilled from calcium hydride.Anhydrous pyridine, dimethylformamide and dimethyl sulfoxide werepurchased from Aldrich and used without purification. n-Butyllithium andt-butyllithium were purchased from Aldrich and standardized by titrationwith diphenylacetic acid.

Unless stated otherwise all reactions were magnetically stirred andmonitored by thin layer chromatography using 0.25 mm E. Merck pre-coatedsilica gel plates. Flash column chromatography was performed with theindicated solvents using silica gel-60 (particle size 0.040-0.062 mm)supplied by E. Merck. Yields refer to chromatographically andspectroscopically pure compounds, unless otherwise stated.

All melting points were determined on a Bristoline heated-stagemicroscope or a Thomas-Hoover apparatus and are corrected. The IR andNMR were obtained for CHCl₃ and CDCl₃ solutions respectively unlessotherwise noted. Infrared spectra were recorded with a Perkin-ElmerModel 283B spectrometer using polystyrene as an external standard.Proton NMR spectra were recorded on a Bruker AM-500 spectrometer.Carbon-13 NMR spectra were recorded on a Bruker AM-500 or AM-250spectrometer. Chemical shifts are reported relative to internaltetramethylsilane (d 0.00) for proton and chloroform δ 77.0) or benzene(δ 128.0) for carbon-13. Optical rotations were obtained with aPerkin-Elmer model 241 polarimeter in the solvent indicated.High-resolution mass spectra were obtained at the University ofPennsylvania Mass Spectrometry Service Center on either a VG micromass70/70H high resolution double-focusing electron impact/chemicalionization spectrometer or a VG ZAB-E spectrometer. Microanalyses wereperformed by Robertson Laboratories, Madison, N.J. Single-crystal X-raydiffraction structure determination were performed at the University ofPennsylvania using an Enraf Nonius CAD-4 automated diffractometer. Highperformance liquid chromatography (HPLC) was performed using a Ranincomponent analytical/semi-prep system.

EXAMPLE 1

Alcohol (−)-8.

p-Methoxybenzyl alcohol (200 g, 1.45 mol) was added to a suspension ofNaH (60% in mineral oil; 5.82 g, 0.146 mol) in anhydrous ether (450 mL)over 1 h at room temperature. The mixture was stirred for 1 h and cooledto 0° C. Trichloroacetonitrile (158 mL, 1.58 mol) was then introducedover 80 min. After 1.5 h the solution was concentrated with the waterbath temperature maintained below 40° C. The residue was treated with amixture of pentane (1.5 L) and MeOH (5.6 mL), stirred at roomtemperature for 30 min, and filtered through a short Celite column.Concentration gave the trichloroimidate (394.3 g) as a red oil which wasused without further purification.

A solution of (R)-(−)-Roche ester (124.7 g, 1.06 mol) inCH₂Cl₂/cyclohexane (1:2, 1.5 L) was cooled to 0° C. and treated withtrichloroimidate (364.3 g) and PPTS (13.3 g, 52.9 mmol). After 3 h, themixture was warmed to room temperature, stirred for 40 h, andconcentrated. Filtration through a short silica column (20% ethylacetate/hexane) afforded the ester (303.5 g) as a slight yellow oil.

The ester (303.5 g) was divided into three portions for the nextreaction. In each preparation, solution of crude ester (112.8 g) inanhydrous THF (1.0 L) was cooled to 0° C. and LiAlH₄ (1.0 M in THF, 560mL, 0.560 mol) was added over 1 h. The mixture was warmed gradually toroom temperature and stirred for 24 h. After dilution with ether (1.0 L)the mixture was cooled to 0° C. and quenched carefully with saturatedaqueous Rochelle's salt (20 mL). The resultant mixture was thentransferred to a 4-L flask, diluted with ether (1.0 L), and treated withadditional Rochelle's solution (ca. 300 mL) with shaking until a solidprecipitated. The solution was filtered, concentrated, and the residue(including the aqueous layer) was diluted with ether (700 mL), driedover Na₂SO₄, filtered and concentrated. The crude products of the threereactions were combined and distilled under vacuum, furnishing (−)-8(142.7 g, 74% yield for two steps) as a colorless oil: [α]²³ _(D) −16.9°© 1.28, CHCl₃); IR (CHCl₃) 3510 (m), 3015 (s), 2965 (s), 2940 (s), 2920(s), 2870 (s), 2840 (m), 1618 (s), 1590 (m), 1517 (s), 1470 (s), 1445(m), 1423 (m), 1365 (m), 1305 (s), 1250 (s), 1178 (s), 1092 (s), 1037(s), 826 (m), 814 (m), 718 (w), 710 (w) cm⁻¹; ¹H NMR (500 MHZ, CDCl₃) d7.23 (d, J=8.6 Hz, 2 H), 6.86 (d, J=8.6 Hz, 2 H), 4.43 (ABq, J_(AB)=11.7Hz, Δδ_(AB)=13.2 Hz, 2 H), 3.78 (s, 3 H), 3.61-3.54 (m, 2 H), 3.53 (ddd,J=9.1, 4.7, 0.8 Hz, 1 H), 3.38 (dd, J=9.1, 7.9 Hz, 1 H), 2.60 (br s, 1H), 2.08-1.98 (m, 1 H), 0.90 (d, J=7.0 Hz, 3 H); ¹³C NMR (125 MHZ,CDCl₃) d 159.2, 130.2, 129.2, 113.8, 75.0, 73.0, 67.7, 55.2, 35.6, 13.4;high resolution mass spectrum (CI, NH₃) m/z 210.1252 [M⁺; calcd forC₁₂H₁₈O₃: 210.1256].

Anal. Calcd for C₁₂H₁₈O₃: C, 68.54; H, 8.63. Found: C, 68.41; H, 8.60.

EXAMPLE 2

Aldol (+)-10.

A solution of DMSO (40.0 mL, 564 mmol) in CH₂Cl₂ (1.0 L) was cooled to−78° C. and oxalyl chloride (23.0 mL, 263 mmol) was added over 1 h.After an additional 15 min, a cooled (−78° C.) solution of alcohol (−)-8(38.0 g, 181 mmol) in CH₂Cl₂ (50 mL) was introduced via a cannula over15 min (20 mL rinse) and the resultant milky mixture was stirred 0.5 hfurther at −78° C. I-Pr₂NEt (150 mL, 861 mmol) was then added over 15min. The mixture was stirred for 30 min, slowly warmed to roomtemperature (70 min), and quenched with aqueous NaHSO₄ (1.0 M, 1.0 L).The organic phase was concentrated, diluted with ether (500 mL), washedwith water (6×500 mL), dried over MgSO₄, filtered and concentrated togive the corresponding aldehyde (38.0 g) as a colorless oil.

A solution of oxazolidinone (+)-9 (44.3 g, 190 mmol) in CH₂Cl₂ (500 mL)was cooled to 0° C. n-Bu₂BOTf (1.0 M in CH₂Cl₂, 199.0 mL, 199 mmol) wasintroduced over 0.5 h, followed by addition of NEt₃ (30.2 mL, 217 mmol)over 10 min. The mixture was stirred at 0° C. for 0.5 h and cooled to−78° C. A precooled (−78° C.) solution of the above aldehyde in CH₂Cl₂(100 mL) was then added via a cannula over 30 min (2×20 mL rinse). After2 h at −78° C. and 2 h at 0° C., the reaction was quenched with pH 7phosphate buffer (200 mL). The mixture was slowly treated with asolution of 30% H₂O₂ in MeOH (1:2, 600 mL) at 0° C., stirred overnightat room temperature, and concentrated. The residue was extracted withethyl acetate (3×250 mL) and the combined extracts were washed withsaturated aqueous NaHCO₃ and water (500 mL each), dried over MgSO₄,filtered and concentrated. Flash chromatography (30% ethylacetate/hexane) provided (+)-10 (70.9 g, 89% yield from 8) as acolorless oil: [α]²³ _(D) +278° © 0.49, CHCl₃); IR (CHCl₃) 3470 (w, br),3020 (m), 2980 (m), 2940 (m), 2920 (m), 2880 (m), 1790 (s), 1705 (m),1620 (m), 1590 (w) 1520 (m), 1485 (w), 1460 (m), 1390 (m), 1360 (m),1305 (w), 1230 (br, s), 1110 (m), 1080 (m), 1035 (m), 985 (m), 970 (m),820 (w), 695 (w) cm⁻¹; ¹H NMR (500 MHZ, CDCl₃) d 7.33-7.30 (m, 2 H),7.27-7.19 (m, 5 H), 6.85 (d, J=8.7 Hz, 2 H), 4.67-4.63 (m, 1 H), 4.42(apparent s, 2 H), 4.14 (apparent d, J=5.0 Hz, 2 H), 3.93 (qd, J=6.9,3.4 Hz, 1 H), 3.85 (ddd, J=8.2, 3.1, 3.1 Hz, 1 H), 3.78 (s, 3 H), 3.69(d, J=2.8 Hz, 1 H), 3.54 (apparent t, J=9.3 Hz, 1 H), 3.54 (dd, J=21.1,9.2 Hz, 1 H), 3.28 (dd, J=13.4, 3.2 Hz, 1 H), 2.76 (dd, J=13.4, 9.6 Hz,1 H), 1.98-1.93 (m, 1 H), 1.25 (d, J=6.9 Hz, 3 H), 0.94 (d, J=7.0 Hz, 3H); ¹³C NMR (125 MHZ, CDCl₃) δ 176.1, 159.2, 153.0, 135.3, 129.9, 129.3,129.2, 128.8, 127.2, 113.7, 75.3, 74.5, 73.1, 66.0, 55.5, 55.2, 40.6,37.7, 35.9, 13.5, 9.7; high resolution mass spectrum (CI, NH₃) m/z442.2243 [(M+H)⁺; calcd for C₂₅H₃₂NO₆: 442.2229].

Anal. Calcd for C₂₅H₃₁NO₆: C, 68.01; H, 7.08. Found: C, 67.81; H, 7.26.

EXAMPLE 3

Common Precursor (+)-5.

A suspension of N,O-Dimethylhydroxylamine hydrochloride (46.9 g, 481mmol) in THF (250 mL) was cooled to 0° C. and AlMe₃ (2.0 M in hexane,240 mL, 480 mmol) was added over 30 min. The resultant solution waswarmed to room temperature, stirred for 0.5 h and then cooled to −30° C.A solution of oxazolidinone (+)-10 (70.9 g, 161 mmol) in THF (150 mL)was introduced over 20 min via cannula (20 mL rinse). After 3 h, thesolution was poured slowly into a mixture of aqueous HCl (1.0 N, 1.2 L)and CH₂Cl₂ (1.0 L) at 0° C. and the mixture was shaken vigorously for 1h. The aqueous phase was extracted with CH₂Cl₂ (2×500 mL) and thecombined organic extracts were washed with water (3×1.0 L), dried overMgSO₄, filtered and concentrated. The crude material was taken up inethyl acetate/hexane (1:3, 150 mL) with vigorous stirring to precipitatemost of the chiral auxiliary. Filtration, concentration and flashchromatography (20% acetone/hexane) afforded (+)-5 (46.2 g, 88% yield)as a colorless oil: [α]²³ _(D) +144° © 0.41, CHCl₃); IR (CHCl₃) 3470 (m,br), 3010 (s), 2975 (s), 2945 (s), 2915 (s), 2870 (s), 2845 (m), 1680(s), 1590 (w), 1515 (s), 1465 (s), 1425 (m), 1390 (m), 1365 (m), 1310(m), 1250 (s), 1180 (s), 1150 (m), 1090 (s), 1040 (s), 1000 (s), 825 (m)cm⁻¹; ¹H NMR (500 MHZ, CDCl₃) δ 7.25 (d, J=8.6 Hz, 2 H), 6.86 (d, J=8.7Hz, 2 H), 4.44 (ABq, J_(AB)=11.6 Hz, Δδ_(AB)=17.1 Hz, 2 H), 3.95 (d,J=2.8 Hz, 1 H), 3.79 (s, 3 H), 3.70 (ddd, J=8.2, 3.2, 3.2 Hz, 1 H), 3.66(s, 3 H), 3.62 (dd, J=9.0, 4.0 Hz, 1 H), 3.53 (dd, J=9.1, 5.9 Hz, 1 H),3.17 (s, 3 H), 3.04 (m, 1 H), 1.91-1.84 (m, 1 H), 1.17 (d, J=7.0 Hz, 3H), 0.98 (d, J=6.9 Hz, 3 H); ¹³C NMR (125 MHZ, CDCl₃) d 178.0, 159.0,130.6, 129.1, 113.7, 113.6, 73.8, 72.8, 72.6, 61.3, 55.1, 36.5, 36.0,14.2, 10.4; high resolution mass spectrum (CI, NH₃) m/z 326.1962[(M+H)⁺; calcd for C₁₇H₂₈NO₅: 326.1967].

Anal. Calcd for C₁₇H₂₇NO₅: C, 62.74; H, 8.36. Found: C, 62.74; H, 8.24.

EXAMPLE 4

Weinreb Amide (−)-11.

A mixture of common precursor (+)-5 (337.3 mg, 1.04 mmol), 4 Å molecularsieves (344 mg), and CH₂Cl₂ (10 mL) was cooled to 0° C. and treated withDDQ (310.3 mg, 1.37 mmol). After 1.5 h, the mixture was filtered througha short Celite column (50% ethyl acetate/hexane) . The filtrate waswashed with saturated aqueous NaHCO₃ and water (100 mL each), dried overMgSO₄, filtered and concentrated. Flash chromatography (30% ethylacetate/hexane) provided (−)-11 (255.6 mg, 76% yield) as a colorlessoil: [α]²³ _(D) −339° © 0.520, CHCl₃); IR (CHCl₃) 3010 (s), 2970 (s),2940 (m), 2880 (m), 2840 (m), 1663 (s), 1620 (s), 1592 (w), 1520 (s),1466 (s), 1447 (m), 1425 (m), 1393 (s), 1375 (s), 1307 (m), 1253 (s),1178 (s), 1120 (s), 1083 (s), 1035 (s), 1015 (m), 1000 (s), 930 (w), 830(m), 700 (w), 660 (w), 620 (w) cm⁻¹; ¹H NMR (500 MHZ, CDCl₃) d 7.41 (d,J=8.8 Hz, 2 H), 6.87 (d, J=8.8 Hz, 2 H), 5.46 (s, 1 H), 4.04 (dd,J=11.3, 4.7 Hz, 1 H), 3.82 (dd, J=9.8, 6.5 Hz, 1 H), 3.79 (s, 3 H), 3.71(s, 3 H), 3.51 (apparent t, J=11.2 Hz, 1 H), 3.19 (s, 3 H), 3.21-3.14(m, 1 H), 1.98-1.92 (m, 1 H), 1.27 (d, J=7.0 Hz, 3 H), 0.75 (d, J=6.8Hz, 3 H); ¹³C NMR (125 MHZ, CDCl₃) d 175.8, 159.8, 131.2, 127.2, 113.5,100.7, 82.8, 72.8, 61.3, 55.3, 39.0, 33.8, 32.6, 13.1, 12.4; highresolution mass spectrum (CI, NH₃) m/z 323.1736 [M+; calcd forC₁₇H₂₅NO₅: 323.1732].

Anal. Calcd for C₁₇H₂₅NO₅: C, 63.14; H, 7.79. Found: C, 63.18; H, 7.74.

EXAMPLE 5

Aldehyde (−)-12.

A solution of amide (−)-11 (2.07 g, 6.40 mmol) in THF (70 mL) was cooledto −78° C. and LiAlH₄ (1.0 M in THF, 3.40 mL, 3.40 mmol) was added over15 min. After 10 min at −78° C. and 10 min at 0° C., the mixture wasquenched with MeOH (1.0 mL), and partitioned between ethyl acetate andsaturated aqueous Rochelle's salt (100 mL each). The organic phase waswashed with brine (100 mL), dried over MgSO₄, filtered and concentrated.Flash chromatography (15% ethyl acetate/hexane) gave (−)-12 (1.38 g, 80%yield) as a colorless oil: [α]²³ _(D) −7.8° © 0.46, CHCl₃); IR (CHCl₃)3015 (m), 2970 (m), 2940 (m), 2840 (m), 1735 (s), 1725 (s), 1615 (m),1590 (w), 1520 (s), 1460 (s), 1390 (m), 1370 (m), 1305 (m), 1250 (s),1170 (s), 1115 (s), 1085 (s), 1035 (s), 990 (m), 960 (m), 830 (m) cm⁻¹;¹H NMR (500 MHZ, CDCl₃) d 9.74 (apparent s, 1 H), 7.32 (d, J=8.8 Hz, 2H), 6.84 (d, J=8.7 Hz, 2 H), 5.46 (s, 1 H), 4.13 (dd, J=11.5, 4.8 Hz, 1H), 4.05 (dd, J=10.4, 2.6 Hz, 1 H), 3.77 (s, 3 H), 3.56 (apparent t,J=11.1 Hz, 1 H), 2.56 (qd, J=7.1, 2.6 Hz, 1 H), 2.15-2.03 (m, 1 H), 1.23(d, J=7.1 Hz, 3 H), 0.80 (d, J=6.7 Hz, 3 H); ¹³C NMR (125 MHZ, CDCl₃) δ204.0, 159.9, 130.7, 127.2, 113.5, 100.9, 81.6, 72.8, 55.2, 47.4, 30.3,11.9, 7.1; high resolution mass spectrum (CI, NH₃) m/z 265.1432 [(M+H)⁺;calcd for C₁₅H₂₁O₄: 265.1439].

EXAMPLE 6

Aldol (+)-13.

A solution of oxazolidinone (+)-9 (21.6 g, 92.7 mmol) in CH₂Cl₂ (200 mL)was cooled to 0° C. and n-Bu₂BOTf (1.0 M in CH₂Cl₂, 86.1 mL, 86.1 mmol)was added over 0.5 h, followed by addition of NEt₃ (15.7 mL, 112.5 mmol)over 10 min. The mixture was stirred at 0° C. for 1 h and cooled to −78°C. A solution of aldehyde (−)-12 (17.5 g, 66.2 mmol) in CH₂Cl₂ (50 mL)was added over 10 min. After additional 20 min at −78° C. and 1 h at 0°C., the reaction was quenched with pH 7 phosphate buffer (100 mL) andMeOH (300 mL), then slowly treated with a solution of 30% H₂O₂ in MeOH(1:1, 100 mL) at 0° C. After 1 h, saturated aqueous Na₂S₂O₃ (100 mL) wasadded. The mixture was concentrated and the residue was extracted withethyl acetate (3×250 mL). The combined extracts were washed withsaturated aqueous Na₂S₂O₃, aqueous NaHCO₃ (10%), brine (200 mL each),dried over MgSO₄, filtered and concentrated. Flash chromatography (10%ethyl acetate/hexane) provided (+)-13 (26.3 g, 80% yield) as whitecrystals: mp 98-100° C.; [α]²³ _(D) +13.5° © 1.19, CHCl₃); IR (CHCl₃)3690 (w), 3520 (w, br), 3020 (m), 2980 (m), 2940 (m), 2880 (w), 2850(m), 1790 (s), 1695 (m), 1620 (m), 1595 (w) 1525 (m), 1505 (w), 1490(w), 1465 (m), 1390 (s), 1365 (m), 1310 (m), 1260-1210 (m, br), 1175(m), 1120 (s), 1085 (m), 1040 (m), 1020 (m), 985 (m), 970 (m), 930 (w),830 (m), 700 (m) cm⁻¹; ¹H NMR (500 MHZ, CDCl₃) d 7.35 (d, J=8.7 Hz, 2H), 7.31 (d, J=7.6 Hz, 2 H), 7.27 (d, J=7.2 Hz, 1 H), 7.19 (d, J=7.7 Hz,2 H), 6.84 (d, J=8.7 Hz, 2 H), 5.45 (s, 1 H), 4.67-4.62 (m, 1 H), 4.14(apparent d, J=5.3 Hz, 2 H), 4.08 (dd, J=11.4, 4.8 Hz, 1 H), 4.07(apparent t, J=4.1 Hz, 1 H), 4.04-3.99 (m, 1 H), 3.76 (s, 3 H), 3.61(dd, J=9.9, 2.2 Hz, 1 H), 3.51 (apparent t, J=11.1 Hz, 1 H), 3.33 (d,J=1.3 Hz, 1 H), 3.21 (dd, J=13.4, 3.4 Hz, 1 H), 2.76 (dd, J=13.4, 9.4Hz, 1 H), 2.12-2.06 (m, 1 H), 1.92-1.86 (m, 1 H), 1.31 (d, J=6.9 Hz, 3H), 1.07 (d, J=7.0 Hz, 3 H), 0.74 (d, J=6.7 Hz, 3 H); ¹³C NMR (125 MHZ,CDCl₃) δ 177.1, 160.0, 152.7, 135.0, 131.0, 129.4, 128.9, 127.40,127.39, 113.6, 101.2, 85.8, 74.5, 73.0, 66.0, 55.2, 54.9, 39.8, 37.7,35.7, 30.4, 12.8, 11.7, 7.8; high resolution mass spectrum (CI, NH₃) m/z497.2410 [M⁺; calcd for C₂₈H₃₅NO₇: 497.2413].

Anal. Calcd for C₂₈H₃₅NO₇: C, 67.58; H, 7.09. Found: C, 67.42; H, 7.02.

EXAMPLE 7

Acetal (+)-14.

A solution of alcohol (+)-13 (26.3 g, 52.9 mmol) and 2,6-lutidine (11.1mL, 95.3 mmol) in CH₂Cl₂ (150 mL) was cooled to −20° C. and TBSOTf (20.5mL, 79.3 mmol) was added over 30 min. After additional 2 h at 0° C., themixture was diluted with ether (300 mL), washed with aqueous NaHSO₄ (1.0M, 200 mL), brine (200 mL), dried over MgSO₄, filtered and concentrated.Flash chromatography (gradient elution, 5%→10% ethyl acetate/hexane)afforded (+)-14 (32.4 g, 100% yield) as a colorless oil: [α]²³ _(D)+20.3° © 1.32, CHCl₃); IR (CHCl₃) 3025 (m), 2970 (m), 2940 (m), 2864(m), 1788 (s), 1705 (m), 1620 (m), 1597 (w),1524 (m), 1503 (w), 1470(m), 1447 (w), 1430 (w), 1395 (s), 1358 (m), 1307 (m), 1255 (s), 1135(m), 1120 (s), 1075 (m), 1030 (m), 985 (m), 976 (m), 930 (m), 865 (m),838 (s), 813 (m), 790 (m), 700 (m) cm⁻¹; ¹H NMR (500 MHZ, CDCl₃) d 7.38(d, J=8.7 Hz, 2 H), 7.30-7.12 (m, 5 H), 6.82 (d, J=8.7 Hz, 2 H), 5.44(s, 1 H), 4.30 (dddd, J=13.4, 7.3, 5.1, 5.1 Hz, 1 H), 4.11 (dd, J=7.1,4.0 Hz, 1 H), 4.02 (dd, J=11.2, 4.7 Hz, 1 H), 3.97 (dq, J=7.0, 7.0 Hz, 1H), 3.80 (dd, J=8.9, 2.3 Hz, 1 H), 3.740 (apparent t, J=4.9 Hz, 1 H),3.738 (s, 3 H), 3.48 (apparent t, J=11.1 Hz, 1 H), 3.27 (apparent t,J=8.2 Hz, 1 H), 3.15 (dd, J=13.4, 3.2 Hz, 1 H), 2.59 (dd, J=13.4, 9.8Hz, 1 H); 2.05 (apparent qd, J=7.4, 4.2 Hz, 1 H), 2.02-1.94 (m, 1 H),1.19 (d, J=6.9 Hz, 1 H), 1.04 (d, J=7.5 Hz, 3 H), 0.92 (s, 9 H), 0.73(d, J=6.7 Hz, 3 H), 0.05 (s, 3 H), 0.04 (s, 3 H); ¹³C NMR (125 MHZ,CDCl₃) d 175.6, 159.9, 152.4, 135.5, 132.0, 129.4, 128.8, 127.8, 127.2,113.4, 100.7, 80.7, 74.6, 73.1, 65.3, 55.3, 55.2, 41.4, 40.9, 37.4,30.6, 26.0, 18.1, 15.0, 12.7, 11.5, −4.0, −4.6; high resolution massspectrum (CI, NH₃) m/z 612.3340 [(M+H)⁺; calcd for C₃₄H₅₀NO₇Si:612.3356].

Anal. Calcd for C₃₄H₄₉NO₇Si: C, 66.74; H, 8.07. Found: C, 66.69; H,7.98.

EXAMPLE 8

Alcohol (−)-15.

A solution of acetal (+)-14 (32.0 g, 52.3 mmol) in THF (600 mL) wascooled to −30° C. and EtOH (6.14 mL, 105 mmol) was added, followed byaddition of LiBH₄ (2.0 M in THF, 52.3 mL, 105 mmol) over 15 min. Afteradditional 1 h at 0° C. and 12 h at room temperature, the mixture wasdiluted with ether (1.0 L), quenched carefully with aqueous NaOH (1.0 N,200 mL) and stirred for 2 h at room temperature. The layers wereseparated and the organic phase was washed with brine (500 mL), driedover Na₂SO₄, filtered and concentrated. Flash chromatography (20% ethylacetate/hexane) provided (−)-15 (18.7 g, 81% yield) as a colorless oil:[α]²³ _(D) −36.1° © 1.15, CHCl₃); IR (CHCl₃) 3630 (w), 3480 (w, br),3010 (m), 2960 (s), 2940 (s), 2885 (m), 2860 (s), 1620 (m), 1594 (w),1523 (s), 1468 (s), 1445 (w), 1430 (w), 1395 (m), 1365 (m), 1307 (m),1255 (s), 1175 (m), 1165 (m), 1150 (m), 1120 (s), 1080 (s), 1030 (s),990 (m), 968 (m), 910 (s), 860 (m), 833 (s), 700 (m), 645 (m) cm⁻¹; ¹HNMR (500 MHZ, CDCl₃) d 7.36 (d, J=8.7 Hz, 2 H), 6.85 (d, J=8.8 Hz, 2 H),5.38 (s, 1 H), 4.08 (dd, J=11.2, 4.7 Hz, 1 H), 3.84 (dd, J=6.7, 1.9 Hz,1 H), 3.77 (s, 3 H), 3.53 (dd, J=9.9, 1.8 Hz, 1 H), 3.55-3.52 (m, 1 H),3.47 (apparent t, J=11.1 Hz, 1 H), 3.44 (dd, J=10.3, 6.2 Hz, 1 H),2.08-1.97 (m, 2 H), 1.94 (dqd, J=7.1, 7.1, 1.7 Hz, 1 H), 1.76 (br s, 1H), 1.02 (d, J=7.1, 3 H), 0.88 (s, 9 H), 0.84 (d, J=6.9 Hz, 3 H), 0.73(d, J=6.7 Hz, 3 H), 0.03 (s, 3 H), 0.00 (s, 3 H); ¹³C NMR (125 MHZ,CDCl₃) d 159.8, 131.4, 127.3, 113.5, 101.0, 82.9, 74.3, 73.3, 66.3,55.2, 38.7, 37.8, 30.7, 26.1, 18.3, 12.2, 11.1, 10.7, −4.0, −4.2; highresolution mass spectrum (CI, NH₃) m/z 439.2889 [(M+H)⁺; calcd forC₂₄H₄₃O₅Si: 439.2879].

Anal. Calcd for C₂₄H₄₂O₅Si: C, 65.71; H, 9.65. Found: C, 65.51; H 9.54.

EXAMPLE 9

Tosylate (−)-16.

A solution of alcohol (−)-15 (5.00 g, 11.4 mmol) in anhydrous pyridine(30 mL) was cooled to 0° C. and treated with TsCl (3.91 g, 20.5 mmol).After 30 min at 0° C. and 5 h at room temperature, the reaction wasquenched with saturated aqueous NaHCO₃ (20 mL). The mixture was dilutedwith ether (200 mL), washed with aqueous NaHSO₄ (1.0 M), aqueous NaHCO₃(10%), brine (200 mL each), dried over MgSO₄, filtered and concentrated.Flash chromatography (10% ethyl acetate/hexane) provided (−)-15 (6.76 g,100% yield) as white solid: mp 71-72° C.; [α]²³ _(D) −23.2° © 1.42,CHCl₃); IR (CHCl₃) 3020 (m), 3000 (m), 2960 (s), 2935 (s), 2880 (m),2855 (s), 1617 (m), 1600 (m), 1590 (m), 1518 (m), 1495 (w), 1462 (s),1390 (m), 1360 (s), 1302 (m), 1250 (s), 1190 (s), 1178 (s), 1120 (s),1098 (s), 1085 (s), 1070 (s, 1032 (s), 963 (s), 900 (m), 830 (s), 810(s), 653 (m); ¹H NMR (500 MHZ, CDCl₃) d 7.70 (d, J=8.3 Hz, 2 H), 7.34(d, J=8.7 Hz, 2 H), 7.25 (d, J=8.8 Hz, 2 H), 6.86 (d, J=8.7 Hz, 2 H),5.36 (s, 3 H), 4.07 (dd, J=11.2, 4.7 Hz, 1 H), 3.85 (dd, J=7.3, 2.7 Hz,1 H), 3.79 (s, 3 H), 3.71 (dd, J=7.1, 1.7 Hz, 1 H), 3.48 (dd, J=9.9, 1.4Hz, 1 H), 3.45 (apparent t, J=11.1 Hz, 1 H), 2.40 (s, 3 H), 2.15 (dqd,J=13.9, 7.0, 1.7 Hz, 1 H), 2.05-1.96 (m, 1 H), 1.83 (dqd, J=7.1, 7.1,1.6 Hz, 1 H), 0.94 (d, J=7.1 Hz, 3 H), 0.82 (s, 9 H), 0.81 (d, J=7.7 Hz,3 H), 0.69 (d, J=6.7 Hz, 3 H), −0.04 (s, 3 H), −0.11 (s, 3 H); ¹³C NMR(125 MHZ, CDCl₃) d 159.8, 144.6, 133.2, 131.3, 129.7, 127.9, 127.3,113.5, 100.9, 82.0, 73.7, 73.2, 73.0, 55.2, 38.4, 35.5, 30.6, 26.0,21.6, 18.3, 12.2, 10.6, 10.3, −3.9, −4.3; high resolution mass spectrum(FAB, NBA) m/z 593.2955 [(M+H)⁺; calcd for C₃₁H₄₉O₇SSi: 593.2968].

EXAMPLE 10

Fragment (−)-A. From Tosylate (−)-16: A solution of Tosylate (−)-16(6.76 g, 11.4 mmol) in anhydrous DMF (50 mL) was treated with NaI (17.1g, 114.0 mmol), heated at 60° C. for 1.5 h, and cooled to roomtemperature. The mixture was diluted with ether (200 mL), washed withwater (200 mL), saturated aqueous Na₂S₂O₃ (100 mL), brine (200 mL),dried over MgSO₄, filtered and concentrated. Flash chromatography (3%ethyl acetate/hexane) provided (−)-A (5.87 g, 94% yield) as a colorlessoil.

From Alcohol (−)-15: A solution of alcohol (−)-15 (4.70 g, 10.7 mmol),PPh₃ (4.21 g, 16.1 mmol) and imidazole (1.09 g, 16.1 mmol) inbenzene/ether (1:2, 75 mL) was treated with I₂ (4.08 g, 16.1 mmol) undervigorous stirring. The mixture was stirred 1 h then diluted with ether(200 mL), washed with saturated Na₂S₂O₃, brine (100 mL each), dried overMgSO₄, filtered and concentrated. Flash chromatography (2% ethylacetate/hexane) furnished (−)-A (5.56 g, 95% yield) as a colorless oil:[α]²³ _(D) −39.3° © 2.01, CHCl₃); IR (CHCl₃) 3015 (m), 2960 (s), 2940(s), 2860 (m), 1620 (w), 1520 (m), 1465 (m), 1430 (w), 1390 (m), 1305(w), 1255 (s), 1230 (m), 1215 (m), 1205 (m), 1170 (m), 1120 (m), 1070(m), 1035 (m), 990 (w), 970 (w), 930 (w), 830 (m) cm⁻¹; ¹H NMR (500 MHZ,CDCl₃) d 7.39 (d, J=8.7 Hz, 2 H), 6.86 (d, J=8.8 Hz, 2 H), 5.40 (s, 1H), 4.09 (dd, J=11.2, 4.7 Hz, 1 H), 3.85 (dd, J=7.1, 1.9 Hz, 1 H), 3.79(s, 3 H), 3.48 (dd, J=8.2, 1.5 Hz, 1 H), 3.47 (apparent t, J=11.1 Hz, 1H), 3.18-3.12 (m, 2 H), 2.11-2.00 (m, 2 H), 1.84 (ddq, J=7.1, 7.1, 1.6Hz, 1 H), 1.02 (d, J=7.1 Hz, 3 H), 0.98 (d, J=6.7 Hz, 3 H), 0.89 (s, 9H), 0.72 (d, J=6.7 Hz, 3 H), 0.06 (s, 3 H); ¹³C NMR (125 MHZ, CDCl₃) d159.8, 131.4, 127.4, 113.4, 100.9, 82.4, 75.5, 73.2, 55.3, 39.6, 38.7,30.7, 26.2, 18.4, 14.7, 14.5, 12.2, 10.7, −3.7, −3.8; high resolutionmass spectrum (CI, NH₃) m/z 548.1833 [(M)⁺; calcd for C₂₄H₄₁IO₄Si:548.1819].

Anal. Calcd for C₂₄H₄₁O₄ISi: C, 52.55; H, 7.53. Found: C, 52.77; H,7.68.

EXAMPLE 11

Amide (+)-17.

A solution of common precursor (+)-5 (12.1 g, 37.2 mmol) and2,6-lutidine (7.80 mL, 70.0 mmol) in CH₂Cl₂ (90 mL) was cooled to 0° C.and tert-Butyldimethylsilyl trifluoromethanesulfonate (12.8 mL, 55.8mmol) was added over 10 min. After 1.5 h, the mixture was diluted withEt₂O (100 mL), washed with aqueous NaHSO₄ (1.0 M), brine (200 mL each),dried over MgSO₄, filtered and concentrated. Flash chromatography (10%ethyl acetate/hexanes) provided (+)-17 (16.4 g, 100% yield) as acolorless oil: [α]²³ _(D) +9.49° 1.47, CHCl₃); IR (CHCl₃) 3018 (s), 2970(s), 2945 (s), 2900 (m), 2870 (s), 1658 (s), 1620 (m), 1592 (w), 1520(s), 1470 (s), 1448 (m), 1425 (m), 1393 (m), 1367 (m), 1308 (m), 1255(s), 1213 (s), 1185 (m), 1178 (m), 1115 (s), 1084 (s), 1042 (s), 1000(s), 940 (w), 928 (w), 871 (s), 839 (s), 770 (s), 726 (s), 664 (m) cm⁻¹;¹H NMR (500 MHZ, CDCl₃) d 7.21 (d, J=8.7 Hz, 2 H), 6.83 (d, J=8.7, 2 H),4.36 (ABq, J_(AB)=11.6 Hz, Δδ_(AB)=17.3 Hz, 2 H), 3.92 (dd, J=8.2, 3.0Hz, 1 H), 3.77 (s, 3 H), 3.55 (s, 3 H), 3.54 (dd, J=9.2, 2.5 Hz, 1 H),3.13 (dd, J=9.2, 7.8 Hz, 1 H), 3.09 (s, 3 H), 3.15-3.09 (m, 1 H),1.92-1.87 (m, 1 H), 1.09 (d, J=7.0 Hz, 3 H), 0.98 (d, J=7.0 Hz, 3 H),0.88 (s, 9 H), 0.04 (apparent s, 6 H); ¹³C NMR (125 MHZ, CDCl₃) d 176.8,159.1, 130.9, 129.2, 113.7, 76.0, 72.7, 71.9, 61.1, 55.2, 39.3, 38.9,26.1, 18.4, 15.3, 15.0, −3.87, −3.93; high resolution mass spectrum (CI,NH₃) m/z 440.2823 [(M+H)⁺; calcd for C₂₃H₄₂NO₅Si: 440.2832].

Anal. Calcd for C₂₃H₄₁NO₅Si: C, 62.83; H, 9.40. Found: C, 63.05; H,9.32.

EXAMPLE 12

Aldehyde (+)-18.

A solution of amide (+)-17 (9.19 g, 20.9 mmol) in THF (350 mL) wascooled to −78° C. and DIBAL (1.0 M in hexane, 44.0 mL, 44.0 mmol) wasadded over 30 min. After 0.5 h at −78° C., the reaction was quenchedwith MeOH (10 mL). The mixture was diluted with ether (500 mL), washedwith saturated aqueous Rochelle's salt, brine (300 mL each), dried overMgSO₄, filtered and concentrated. Flash chromatography (10% ethylacetate/hexane) gave (+)-18 (7.05 g, 89% yield) as a colorless oil:[α]²³ _(D) +23.2° © 1.49, CHCl₃); IR (CHCl₃) 2960 (s), 2930 (s), 2860(s), 1730 (s), 1610 (m), 1583 (w), 1510 (m), 1460 (m), 1373 (m), 1360(w), 1300 (m), 1245 (s), 1170 (m), 1085 (m), 1033 (s), 933 (w), 835 (s)cm⁻¹; ¹H NMR (500 MHZ, CDCl₃) d 9.67 (d, J=0.9 Hz, 1 H), 7.22 (d, J=8.7Hz, 2 H), 6.86 (d, J=8.7 Hz, 2 H), 4.37 (ABq, J_(AB)=11.6 Hz,Δδ_(AB)=23.6 Hz, 2 H) 4.18 (dd, J=6.1, 3.7 Hz, 1 H), 3.78 (s, 3 H), 3.41(dd, J=9.2, 5.7 Hz, 1 H), 3.31 (dd, J=9.2, 6.0 Hz, 1 H), 2.47 (qdd,J=7.1, 3.7, 0.9 Hz, 1 H), 2.03-1.95 (m, 1 H), 1.08 (d, J=7.0 Hz, 3 H),0.94 (d, J=7.0 Hz, 3 H), 0.84 (s, 9 H), 0. 04 (s, 3 H), −0.03 (s, 3 H);¹³C NMR (125 MHZ, CDCl₃) d 204.8, 159.2, 130.5, 129.2, 113.8, 72.7,72.4, 71.7, 55.3, 50.0, 38.3, 25.9, 18.2, 14.3, 8.4, −4.1, −4.4; highresolution mass spectrum (FAB, NBA) m/z 403.2304 [(M+Na)⁺; calcd forC₂₁H₃₆O₄SiNa: 403.2280].

EXAMPLE 13

Bromo Ester 19.

A solution of aldehyde (+)-18 (822.1 mg, 2.16 mmol) in benzene (20 mL)was treated with Ph₃P═CBrCO₂Et (2.28 g, 5.34 mmol), heated at reflux for40 h and cooled to room temperature. The mixture was filtered through ashort silica column (20% ethyl acetate/hexane) and concentrated. Flashchromatography (3% ethyl acetate/hexane) afforded Z-Bromo ester (−)-19(861.4 mg, 75% yield) and E-Bromo Ester (+)-19 (101.0 mg, 8.8% yield).

Z-Bromo Ester (−)-19: Colorless oil; [α]²³ _(D) −6.38° © 1.85, CHCl₃);IR (CHCl₃) 2960 (s), 2940 (s), 2860 (s), 1725 (s), 1618 (m), 1590 (w),1515 (s), 1468 (m), 1390 (m), 1370 (m), 1303 (m), 1250 (s, br), 1176(m), 1090 (s), 1037 (s), 1008 (m), 950 (m), 940 (m), 840 (s) cm⁻¹; ¹HNMR (500 MHZ, C₆D₆) d 7.45 (d, J=9.7 Hz, 1 H), 7.26 (d, J=8.6 Hz, 2 H),6.80 (d, J=8.7 Hz, 2 H), 4.37 (ABq, J_(AB)=11.6 Hz, Δδ_(AB)=19.3 Hz, 2H), 3.99, (dq, J=10.8, 7.1 Hz, 1 H), 3.94 (dq, J=10.8, 7.1 Hz, 1 H),3.82 (apparent t, J=5.4 Hz, 1 H), 3.41 (dd, J=9.1, 6.3 Hz, 1 H), 3.31(s, 3 H), 3.30 (dd, J=9.2, 6.5 Hz, 1 H), 3.13-3.06 (m, 1 H), 2.05(apparent septet, J=6.9 Hz, 1 H), 1.013 (d, J=7.0 Hz, 3 H), 1.006 (d,J=6.8 Hz, 3 H), 0.97 (s, 9 H), 0.92 (apparent t, J=7.1 Hz, 3 H), 0.06(s, 3 H), 0.05 (s, 3 H); ¹³C NMR (125 MHZ, CDCl₃) d 162.5, 159.1, 149.6,130.8, 129.0, 114.9, 113.7, 75.5, 72.6, 72.2, 62.4, 55.3, 40.2, 38.9,26.0, 18.3, 14.2, 14.1, 13.7, −4.0, −4.2; high resolution mass spectrum(CI, NH₃) m/z 546.2270 [(M+NH₄)⁺; calcd for C₂₅H₄₅NO₅BrSi: 546.2251].

Anal. Calcd for C₂₅H₄₁O₅BrSi: C, 56.70; H, 7.80. Found: C, 56.96; H,7.86.

E-Bromo Ester (+)-19. Colorless oil; [α]²³ _(D) +3.2° © 1.65, CHCl₃); IR(CHCl₃) 2965 (s), 2940 (s), 2905 (m), 2890 (m), 2865 (s), 1720 (s), 1617(m), 1590 (w), 1518 (s), 1468 (s), 1375 (s), 1350 (m), 1305 (m), 1250(s, br), 1177 (m), 1090 (s), 1035 (s), 1007 (m), 950 (m), 840 (s), 675(w) cm⁻¹; ¹H NMR (500 MHZ, CDCl₃) d 7.23 (d, J=8.6 Hz, 2 H), 6.86 (d,J=8.7 Hz, 2 H), 6.56 (d, J=10.6 Hz, 1 H), 4.39 (apparent s, 2 H), 4.24(dq, J=10.8, 7.1 Hz, 1 H), 4.2.2 (dq, J=10.8, 7.1 Hz, 1 H), 3.79 (s, 3H), 3.61 (dd, J=5.5, 5.0 Hz, 1 H), 3.43, (dd, J=9.2, 5.5 Hz, 1 H),3.39-3.32 (m, 1 H), 3.24 (dd, J=9.1, 7.2 Hz, 1 H), 1.98-1.90 (m, 1 H),1.30 (apparent t, J=7.1 Hz, 1 H), 1.00 (d, J=6.7 Hz, 3 H), 0.94 (d,J=7.0 Hz, 3 H), 0.89 (s, 9 H), 0.05 (s, 3 H), 0.03 (s, 3 H); ¹³C NMR(125 MHZ, CDCl₃) d 162.8, 159.1, 151.9, 130.8, 129.1, 113.7, 110.2,76.3, 72.6, 72.2, 62.1, 55.2, 38.8, 26.1, 18.3, 14.7, 14.1, 13.9, −4.06,−4.10; high resolution mass spectrum (CI, NH₃) m/z 529.1982 [(M+H)⁺;calcd for C₂₅ H₄₂BrO₅Si: 529.1985].

Anal. Calcd for C₂₅H₄₁O₅BrSi: C, 56.70; H, 7.80. Found: C, 56.83; H,7.99.

EXAMPLE 14

Allylic Alcohol (−)-20.

A solution of ester (−)-19 (858.4 mg, 1.62 mmol) in CH₂Cl₂ (16 mL) wascooled to −78° C. and DIBAL (1.0 M in hexane, 3.60 mL, 3.60 mmol) wasadded over 10 min. After 5 min at −78° C. and 10 min at roomtemperature, the reaction was quenched with MeOH (200 mL), followed byaddition of saturated aqueous Rochelle's salt dropwise with stirringuntil a solid precipitated. The solution was separated by decanting(3×30 mL rinse, ethyl acetate) and the combined organic solutions weredried over MgSO₄, and concentrated. Flash chromatography (10% ethylacetate/hexane) provided (−) -20 (674.5 mg, 85% yield) as a colorlessoil: [α]²³ _(D) −15.5° © 2.51, CHCl₃); IR (CHCl₃) 3600 (w), 3420 (w,br), 3010 (m), 2960 (s), 2940 (s), 2890 (m), 2860 (s), 1618 (m), 1590(w), 1520 (s), 1470 (m), 1380 (m), 1315 (m), 1307 (m), 1255 (s), 1178(m), 1085 (s), 1039 (s), 1010 (m), 972 (m), 940 (m), 840 (s), 675 (m),660 (m) cm⁻¹; ¹H NMR (500 MHZ, CDCl₃) d 7.24 (d, J=8.7 Hz, 2 H), 6.87(d, J=8.7 Hz, 2 H), 5.88 (br d, J=9.3 Hz, 1 H), 4.39 (ABq, J_(AB)=11.6Hz, Δδ_(AB)=18.3 Hz, 2 H), 4.16 (apparent d, J=5.6 Hz, 2 H), 3.79 (s, 3H), 3.59 (apparent t, J=5.3 Hz, 1 H), 3.48 (dd, J=9.2, 5.3 Hz, 1 H),3.23 (dd, J=9.2, 7.7 Hz, 1 H), 2.82-2.76 (m, 1 H), 2.00-1.92 (m, 1 H),0.98 (d, J=6.9 Hz, 3 H), 0.97 (d, J=6.8 Hz, 3 H), 0.88 (s, 9 H), 0.024(s, 3 H), 0.016 (s, 3 H); ¹³C NMR (125 MHZ, CDCl₃) d 159.1, 134.1,130.9, 129.1, 125.1, 113.7, 76.5, 72.6, 72.3, 68.4, 55.3, 39.1, 38.7,26.1, 18.4, 14.9, 14.3, −3.9, −4.0; high resolution mass spectrum (CI,NH₃) m/z 487.1873 [(M+H)⁺; calcd for C₂₃H₄₀O₄BrSi: 487.1879].

Anal. Calcd for C₂₃H₃₉O₄BrSi: C, 56.66; H, 8.06. Found: C, 56.72; H,8.07.

EXAMPLE 15

Mesylate (−)-21.

A solution of alcohol (−)-20 (6.85 g, 14.1 mmol) in CH₂Cl₂ (150 mL) wascooled to 0° C. and MsCl (2.20 mL, 28.4 mmol) was added over 2 min.After 10 min, the reaction was quenched with aqueous NaHSO₄ (1.0 M, 100mL). The organic phase was washed with water (100 mL), dried over MgSO₄,and concentrated. Flash chromatography (10% ethyl acetate/hexane)afforded (−)-21 (7.85 g, 99% yield) as a colorless oil: [α]²³ _(D)−14.6° © 1.40, CHCl₃); IR (CHCl₃) 3020 (m), 2960 (s), 2940 (s), 2880(m), 2860 (s), 1730 (w), 1610 (m), 1583 (m), 1510 (s), 1460 (m), 1410(m), 1362 (s), 1300 (m), 1250 (s), 1220 (s), 1175 (s), 1080 (s), 1032(s), 1002 (m), 960 (m), 937 (s), 835 (s) cm⁻¹; ¹H NMR (500 MHZ, CDCl₃) d7.23 (d, J=8.6 Hz, 2 H), 6.86 (d, J=8.6 Hz, 2 H), 6.07 (d, J=9.4 Hz, 1H), 4.74 (d, J=0.4 Hz, 2 H), 4.38 (ABq, J_(AB)=11.7 Hz, Δδ_(AB)=25.5 Hz,2 H), 3.79 (s, 3 H), 3.61 (apparent t, J=5.2 Hz, 1 H), 3.44 (dd, J=9.2,5.7 Hz, 1 H), 3.22 (dd, J=9.2, 7.3 Hz, 1 H), 3.01 (s, 3 H), 2.84-2.77(m, 1 H), 1.99-1.91 (m, 1 H), 0.98 (d, J=6.8 Hz, 3 H), 0.96 (d, J=7.0Hz, 3 H), 0.88 (s, 9 H), 0.03 (s, 3 H), 0.02 (s, 3 H); ¹³C NMR (125 MHZ,CDCl₃) d 159.1, 140.9, 130.8, 129.1, 116.7, 113.8, 76.1, 74.2, 72.6,72.1, 55.3, 39.6, 38.8, 38.5, 26.0, 18.3, 14.7, 14.3, −3.9, −4.0; highresolution mass spectrum (CI, NH₃) m/z 582.1911 [(M+NH₄)⁺; calcd forC₂₄H₄₅NO₆BrSSi: 582.1920].

EXAMPLE 16

Vinyl Bromide (−)-22.

A solution of mesylate (−)-21 (6.43 g, 11.4 mmol) in benzene (120 mL)was treated with LiBHEt₃ (1.0 M in THF, 25.0 mL, 25.0 mmol) at roomtemperature. After 0.5 h, the reaction was quenched with aqueous NaOH(1.0 N, 50 mL). The mixture was diluted with ethyl acetate (200 mL),washed with brine (2×200 mL), dried over MgSO₄, filtered andconcentrated. Flash chromatography (5% ethyl acetate/hexane) provided(−)-22 (4.86 g, 91%) as a colorless oil: [α]²³ _(D) −16.9° © 1.69,CHCl₃); IR (CHCl₃) 3005 (m), 2965 (s), 2935 (s), 2860 (s), 1660 (w),1610 (m), 1585 (w), 1510 (m), 1460 (m), 1425 (w), 1377 (m), 1360 (m),1300 (m), 1250 (s), 1180 (m), 1170 (m), 1075 (s), 1030 (m), 860 (m), 835(s), 805 (m), 660 (w) cm⁻¹; ¹H NMR (500 MHZ, CDCl₃) d 7.24 (d, J=8.6 Hz,2 H), 6.86 (d, J=8.6 Hz, 2 H), 5.47 (apparent dd, J=9.0, 1.2 Hz, 1 H),4.39 (ABq, J_(AB)=11.7 Hz, Δδ_(AB)=15.8 Hz, 2 H), 3.79 (s, 3 H), 3.56(apparent t, J=5.4 Hz, 1 H), 3.50 (dd, J=9.1, 5.1 Hz, 1 H), 3.22 (dd,J=8.8, 8.1 Hz, 1 H), 2.74-2.67 (m, 1 H), 2.21 (d, J=1.1 Hz, 3 H),1.99-1.91 (m, 1 H), 0.98 (d, J=6.9 Hz, 3 H), 0.94 (d, J=6.8 Hz, 3 H),0.88 (s, 9 H), 0.01 (s, 3 H), 0.00 (s, 3 H); ¹³C NMR (125 MHZ, CDCl₃) d159.1, 133.4, 131.0, 129.1, 120.6, 113.7, 76.7, 72.6, 72.5, 55.3, 39.7,38.7, 28.8, 26.1, 18.4, 14.8, 14.4, −3.96, −4.01; high resolution massspectrum (FAB, NBA) m/z 493.1763 [(M+Na)⁺; calcd for C₂₃H₃₉O₃BrSiNa:493.1750].

EXAMPLE 17

Vinyl Silane (−)-23.

A solution of vinyl bromide (−)-22 (83.2 mg, 0.177 mmol) in THF (2.0 mL)was cooled to −78° C. and n-BuLi (1.6 M in hexane, 260 ml, 416 mmol) wasadded over 10 min. After 1 h at −78° C. and 15 min at room temperature,the reaction was quenched with H₂O (200 mL). The mixture wasconcentrated and dissolved in ethyl acetate (30 mL), washed with water(30 mL), dried over MgSO₄, filtered and concentrated. Flashchromatography (5% ethyl acetate/hexane) provided (−)-23 (47.9 mg, 69%yield) as a colorless oil: [α]²³ _(D) −61.5° 0.615, CHCl₃); IR (CHCl₃)3680 (w), 3470 (m, br), 1614 (m), 1588 (w), 1513 (s), 1465 (m), 1442(m), 1415 (m), 1360 (m), 1302 (m), 1250 (s), 1176 (m), 1120 (m), 1077(m), 1032 (m), 992 (m), 830 (s), 820 (s), 805 (s) cm⁻¹; ¹H NMR (500 MHZ,CDCl₃) d 7.22 (d, J=8.7 Hz, 2 H), 6.85 (d, J=8.7 Hz, 2 H), 6.22 (dq,J=10.5, 1.6 Hz, 1 H), 4.42 (ABq, J_(AB)=11.4 Hz, Δδ_(AB)=18.8 Hz, 2 H),3.78 (s, 3 H), 3.65 (br s, 1 H), 3.56 (dd, J=9.1, 4.0 Hz, 1 H), 3.44(dd, J=8.8, 2.9 Hz, 1 H), 3.42 (apparent t, J=8.8 Hz, 1 H), 2.45 (dqd,J=10.3, 6.6, 2.7 Hz, 1 H), 1.95-1.87 (m, 1 H), 1.78 (d, J=1.6 Hz, 3 H),0.91 (d, J=6.7 Hz, 3 H), 0.87 (s, 9 H), 0.80 (d, J=7.0 Hz, 3 H), 0.09(s, 3 H), 0.08 (s, 3 H); ¹³C NMR (125 MHZ, CDCl₃) d 159.4, 147.7, 130.8,129.7, 129.4, 113.9, 79.9, 76.4, 73.3, 55.3, 38.1, 36.3, 27.1, 26.6,17.8, 13.4, 13.1, −3.4, −3.7; high resolution mass spectrum (CI, NH₃)m/z 393.2821 [(M+H)⁺; calcd for C₂₃H₄₁O₃Si: 393.2824].

Anal. Calcd for C₂₃H₄₀O₃Si: C, 70.36; H, 10.27. Found: C, 70.58; H,10.57.

EXAMPLE 18

trans Olefin (+)-24.

A solution of vinyl bromide (−)-22 (27.8 mg, 0.0591 mmol) in ether (600μL) was cooled to −78° C., and t-BuLi (1.7 M in pentane, 103 μL, 0.175mmol) was added over 2 min. After 10 min at −78° C. and 5 min at roomtemperature, the reaction was quenched with MeOH (100 mL). The mixturewas filtered through a short silica plug, and concentrated. Flashchromatography (1% ethyl acetate/hexane) provided (+)-24 (21.9 mg, 94%yield). as a colorless oil; [α]²³ _(D) +19.3° © 1.10, CHCl₃); IR (CHCl₃)3000 (m), 2960 (s), 2935 (s), 2880 (m), 2860 (s), 1612 (m), 1587 (w),1510 (s), 1462 (m), 1440 (m), 1405 (w), 1375 (m), 1360 (m), 1300 (m),1250 (s), 1170 (m), 1090 (s), 1034 (s), 1002 (m), 970 (m), 934 (w), 850(m), 832 (s), 720 (m) cm⁻¹; ¹H NMR (500 MHZ, C₆D₆) d 7.24 (d, J=8.7 Hz,2 H), 6.80 (d, J=8.6 Hz, 2 H), 5.43 (ddq, J=15.3, 7.8, 1.4 Hz, 1 H),5.34 (dqd, J=15.4, 6.3, 0.7 Hz, 1 H), 4.38 (ABq, J_(AB)=11.7 Hz,Δδ_(AB)=30.7 Hz, 2 H), 3.58 (apparent t, J=5.2 Hz, 1 H), 3.57 (dd,J=9.0, 5.1 Hz, 1 H), 3.36 (dd, J=9.0, 7.2 Hz, 1 H), 3.30 (s, 3 H), 2.39(ddq, J=6.8, 6.8, 6.8 Hz, 1 H), 2.17-2.10 (m, 1 H), 1.58 (apparent d,J=6.1 Hz, 3 H), 1.07 (d, J=7.2 Hz, 3 H), 1.05 (d, J=6.9 Hz, 3 H), 1.00(s, 9 H), 0.10 (s, 3 H), 0.08 (s, 3 H); ¹³C NMR (125 MHZ, CDCl₃) d159.0, 135.6, 131.1, 129.1, 123.9, 113.7, 78.4, 72.6, 72.5, 55.3, 40.4,37.9, 26.2, 26.1, 18.4, 18.0, 15.9, 15.1, −3.8, −4.1; high resolutionmass spectrum (CI, NH₃) m/z 393.2836 [(M+H)⁺; calcd for C₂₃H₄₁O₃Si:393.2824].

EXAMPLE 19

Alcohol (−)-25.

A solution of PMB ether (−)-22 (50.0 mg, 0.106 mmol) and PMB acetal(−)-15 (46.5 mg, 0.106 mmol) in CH₂Cl₂ (2.0 mL) was cooled to 0° C.,then treated with H₂O (100 mL) and DDQ (26.5 mg, 0.117 mmol). After 30min, the mixture was diluted with ether (60 mL), washed with saturatedaqueous NaHCO₃ (60 mL), brine (3×60 mL), dried over MgSO₄, filtered andconcentrated. Flash chromatography (gradient elution, 5%→10% ethylacetate/hexane) afforded (−)-25 (31.0 mg, 83%. yield) and recovered(−)-15 (40.0 mg, 86% recovery).

(−)-25: [α]²³ _(D) −13.3° © 0.99, CHCl₃); IR (CHCl₃) 3640 (w), 3520 (m),3000 (m), 2960 (s), 2940 (s), 2890 (m), 2860 (s), 1660 (w), 1472 (m),1465 (m), 1440 (m), 1407 (m), 1390 (m), 1380 (m), 1360 (m), 1258 (s),1072 (s), 1023 (s), 1005 (s), 980 (m), 937 (m), 847 (s) cm⁻¹; ¹H NMR(500 MHZ, CDCl₃) d 5.50 (apparent dd, J=9.0, 1.1 Hz, 1 H), 3.65 (dd,J=11.0, 4.8 Hz, 1 H), 3.59 (dd, J=11.0, 5.7 Hz, 1 H), 3.56 (apparent t,J=5.2 Hz, 1 H), 2.80- 2.72 (m,1 H), 2.25 (d, J=1.0 Hz, 3 H), 2.20 (br s,1 H),1.86-1.78 (m, 1 H), 0.99 (d, J=7.1 Hz, 3 H), 0.98 (d, J=6.9 Hz, 3H), 0.90 (s, 9 H), 0.09 (s, 3 H), 0.05 (s, 3 H); ¹³C NMR (125 MHZ,CDCl₃) d 132.6, 121.7, 79.7; 65.6, 40.9, 38.8, 28.9, 26.1, 18.3, 15.5,15.0, −3.9, −4.0; high resolution mass spectrum (CI, NH₃) m/z 351.1087[M⁺; calcd for C₁₅H₃₁O₂BrSi: 351.1093].

EXAMPLE 20

Alcohol (+)-26.

A solution of amide (+)-17 (323.5 mg, 0.738 mmol) in EtOH (8.0 mL) wasstirred for 5 h under H₂ atmosphere in the presence of Pearlman'scatalyst (20% Pd(OH)₂/C, 104.1 mg), then filtered and concentrated.Flash chromatography (10 mL silica, 20% ethyl acetate/hexane) provided(+)-26 (216.7 mg, 92% yield) as a colorless oil: [α]²³ _(D) +16.1° ©2.60, CHCl₃); IR (CHCl₃) 3480 (m, br), 3000 (s), 2958 (s), 2935 (s),2880 (s), 2860 (s), 1635 (s), 1460 (s), 1415 (m), 1390 (s), 1360 (m),1285 (w), 1255 (s), 1174 (m), 1148 (m), 1093 (s), 1070 (s), 1047 (s),1033 (s), 990 (s), 935 (m), 905 (w), 860 (s), 830 (s) cm⁻¹; ¹H NMR (500MHZ, CDCl₃) d 4.05 (dd, J=9.1, 3.1 Hz, 1 H), 3.69 (s, 3 H), 3.55-3.50(m, 1 H), 3.23 (ddd, J=10.1, 10.1, 2.8 Hz, 1 H), 3.13 (s, 3 H), 3.09 (brm, 1 H), 2.81 (br m, 1 H), 1.91-1.83 (m, 1 H), 1.14 (d, J=7.0 Hz, 3 H),0.879 (d, J=7.0 Hz, 3 H), 0.879 (s, 9 H), 0.08 (s, 3 H), 0.06 (s, 3 H);¹³C NMR (125 MHZ, CDCl₃) d 177.3, 75.2, 64.9, 61.5, 40.8, 38.2, 32.2,26.0, 18.2, 15.9, 12.8, −4.1, −4.3; high resolution mass spectrum (CI,NH₃) m/z 320.2265 [(M+H)⁺; calcd for C₁₅H₃₄NO₄Si: 320.2256].

EXAMPLE 21

Aldehyde (+)-27.

A solution of alcohol (+)-26 (8.80 g, 27.5 mmol) and NEt₃ (15.3 mL, 110mmol) in CH₂Cl₂ (50 mL) was cooled to −10° C. and treated with SO₃.pyr(13.1 g, 82.6 mmol) in DMSO (100 mL). After 20 min at room temperature,the mixture was diluted with ether (300 mL), washed with aqueous NaHSO₄(1.0 M, 200 mL), brine (4×200 mL), dried over MgSO₄, filtered andconcentrated. Flash chromatography (20% ethyl acetate/hexane). afforded(+)-27 (8.55 g, 98% yield) as a colorless oil: [α]²³ _(D) +51.2° © 1.00,CHCl₃); IR (CHCl₃) 3010 (m), 2960 (s), 2940 (s), 2895 (m), 2865 (m),1750 (m), 1720 (s), 1647 (s), 1460 (s), 1420 (m), 1390 (s), 1360 (m),1255 (s), 1180 (m), 1105 (m), 1077 (m), 1040 (s), 995 (s), 936 (m), 853(s), 837 (s), 710 (m), 657 (m) cm⁻¹; ¹H NMR (500 MHZ, CDCl₃) d 9.68 (d,J=1.6 Hz, 1 H), 4.22 (dd, J=8.9, 2.6 Hz, 1 H), 3.68 (s, 3 H), 3.10(apparent s, 4 H), 2.46 (qdd, J=7.1, 2.6, 1.5 Hz, 1 H), 1.16 (d, J=6.9Hz, 3 H), 1.10 (d, J=7.0 Hz, 3 H), 0.88 (s, 9 H), 0.092 (s, 3 H), 0.088(s, 3 H); ¹³C NMR (125 MHZ, CDCl₃) d 203.2, 175.6, 75.1, 61.5, 52.1,39.6, 32.1, 25.9, 18.2, 15.4, 10.2, −4.07, −4.11; high resolution massspectrum (CI, NH₃) m/z 318.2096 [(M+H)⁺; C₁₅H₃₂NO₄Si: 318.2100].

EXAMPLE 22

Dithiane (+)-28.

A solution of ZnCl₂ (dried at 140° C. for 1 h under vacuum, 170.5 mg,1.25 mmol) in ether (6.0 mL) was cooled to 0° C. and (TMSSCH₂)₂CH₂(175.0 μL, 0.628 mmol) was added. The resultant white milky suspensionwas treated with aldehyde (+)-27 (180.0 mg, 0.567 mmol) in ether (6.0mL). The mixture was stirred for 4.5 h at 0° C. and 1.5 h at roomtemperature, then partitioned between ethyl acetate (50 mL) and aqueousammonia (30 mL). The organic phase was washed with brine (2×30 mL),dried over MgSO₄, filtered and concentrated. Flash chromatography (10%ethyl acetate/hexane) provided (+)-28 (182.9 mg, 79% yield) as a whitesolid: mp 55-57° C.; [α]²³ _(D) +18.5° © 1.44, CHCl₃); IR (CHCl₃) 3015(m), 2970 (s), 2945 (s), 2910 (m), 2870 (m), 1665 (s), 1475 (m), 1470(m), 1437 (m), 1430 (m), 1420 (m), 1390 (m), 1365 (m), 1320 (w), 1280(m), 1260 (m), 1120 (m), 1115 (m), 1097 (m), 1080 (m), 1065 (m), 1040(m), 1000 (m), 940 (w), 925 (w), 910 (w), 877 (m), 838 (s), 815 (m), 800(m), 700 (w), 675 (w), 660 (w) cm⁻¹; ¹H NMR (500 MHZ, CDCl₃) d 4.33 (d,J=4.2 Hz, 1 H), 4.23 (dd, J=7.1, 3.6 Hz, 1 H), 3.68 (s, 3 H), 3.15 (s, 3H), 2.98 (dq, J=6.8, 3.7 Hz, 1 H), 2.90 (ddd, J=14.1, 12.2, 2.5 Hz, 1H), 2.83-2.77 (m, 3 H), 2.09-2.03 (m, 1 H), 1.94 (ddq, J=7.2, 7.2, 4.3Hz, 1 H), 1.88-1.76 (m, 1 H), 1.08 (d, J=7.2 Hz, 3 H), 1.07 (d, J=6.9Hz, 3 H), 0.90 (s, 9 H), 0.13 (s, 3 H), 0.02 (s, 3 H); ¹³C NMR (125 MHZ,CDCl₃) d 176.2, 73.2, 61.0, 50.8, 44.2, 38.6, 31.3, 30.3, 26.2, 18.4,12.9, 11.0, −4.1, −4.2; high resolution mass spectrum (CI, NH₃) m/z408.2081 [(M+H)⁺; calcd for C₁₈H₃₈NO₃S₂Si: 408.2062].

Anal. Calcd. for C₁₈H₃₇NO₃S₂Si: C, 53.03; H, 9.15. Found: C, 53.06; H,9.31.

EXAMPLE 23

Aldehyde (+)-29.

A solution of dithiane (+)-28 (1.05 g, 2.58 mmol) in THF (40 mL) wascooled to −78° C. and DIBAL (1.0 M in hexane, 5.15 mL, 5.15 mmol) wasadded over 15 min. After 10 min at −78° C., the mixture was quenchedwith MeOH (2.0 mL) and partitioned between ether and saturated aqueousRochelle's salt (50 mL each). The organic phase was washed with brine(30 mL), dried over MgSO₄, filtered and concentrated. Flashchromatography (10% ethyl acetate/hexane) provided (+)-29 (822 mg, 91%yield) as white solid: mp 54-55° C.; [α]²³ _(D) +50.8° © 1.19, CHCl₃);IR (CHCl₃) 2965 (s), 2940 (s), 2910 (s), 2865 (s), 2720 (w), 1730 (s),1475 (m), 1467 (m), 1428 (m), 1418 (m), 1390 (m), 1365 (m), 1280 (m),1260 (s), 1190 (m), 1150 (m), 1104 (s), 1070 (m), 1030 (s), 1007 (m),953 (m), 940 (m), 910 (m), 835 (s), 810 (m), 675 (m) cm³¹ ¹; ¹H NMR (500MHZ, CDCl₃) d 9.70 (s, 1 H), 4.44 (dd, J=8.3, 2.2 Hz, 1 H), 4.38 (d,J=3.7 Hz, 1 H), 2.93 (ddd, J=14.1, 12.3, 2.6 Hz, 1 H), 2.84-2.80 (m, 3H), 2.43 (qd, J=7.1, 2.2 Hz, 1 H), 2.13-2.07 (m, 1 H), 2.02 (dqd, J=8.2,7.1, 3.7 Hz, 1 H), 1.88-1.79 (m, 1 H), 1.10 (d, J=6.9 Hz, 3 H), 1.05 (d,J=7.1 Hz, 3 H), 0.87 (s, 9 H), 0.16 (s, 3 H), −0.01 (s, 3 H); ¹³C NMR(125 MHZ, CDCl₃) d 204.6, 71.1, 51.0, 49.7, 43.5, 31.3, 30.3, 26.2,26.0, 18.4, 12.9, 6.8, −3.9, −4.3; high resolution mass spectrum (CI,NH₃) m/z 349.1678 [(M+H)⁺; calcd for C₁₆H₃₃O₂S₂Si: 349.1691].

Anal. Calcd for C₁₆H₃₂O₂S₂Si: C, 55.12; H, 9.25. Found: C, 55.08; H,9.28.

EXAMPLE 24

Dimethoxy Acetal (+)-30.

A solution of aldehyde (+)-29 (792 mg, 2.27 mmol) in HC(OMe)₃/MeOH (48mL, 1:5) was treated with TsOH.H₂O (8.6 mg, 0.045 mmol) at roomtemperature. After 30 min, NEt₃ (1.0 mL) was added and the mixture wasconcentrated. Flash chromatography (10% ethyl acetate/hexane) provided(+)-30 (886 mg, 99% yield) as a white solid: mp 58-59° C.; [α]²³ _(D)+27.1° © 2.85, CHCl₃); IR (CHCl₃) 2960 (s), 2940 (s), 2905 (s), 2860(m), 2835 (m), 1473 (m), 1463 (m), 1432 (m), 1425 (m), 1415 (m), 1387(m), 1362 (m), 1340 (w), 1278 (m), 1252 (s), 1190 (m), 1158 (m), 1104(s), 1070 (m), 1050 (m), 1030 (s), 1005 (m), 963 (m), 938 (m), 908 (m),873 (m), 834 (s), 810 (m) cm⁻¹; ¹H NMR (500 MHZ, CDCl₃) d 4.41 (d, J=3.1Hz, 1 H), 4.23 (d, J=8.6 Hz, 1 H), 4.02 (dd, J=8.6, 1.3 Hz, 1 H), 3.29(s, 3 H), 3.26 (s, 3 H), 2.93 (ddd, J=14.0, 12.4, 2.5 Hz, 1 H),2.85-2.78 (m, 3 H), 2.11-2.05 (m, 1 H), 1.93-1.77 (m, 3 H), 1.00 (d,J=7.2 Hz, 3 H), 0.91 (s, 9 H), 0.85 (d, J=6.9 Hz, 3 H), 0.17 (s, 3 H),0.09 (s, 3 H); ¹³C NMR (125 MHZ, CDCl₃) d 105.0, 71.5, 53.0, 51.5, 51.2,43.8, 37.4, 31.3, 30.2, 26.3, 18.8, 12.9, 8.1, −3.8, −4.3; highresolution mass spectrum (FAB, NBA) m/z 417.1934 [(M+Na)⁺; calcd forC₁₈H₃₈O₃S₂SiNa: 417.1930].

Anal. Calcd for C₁₈H₃₈O₃S₂Si: C, 54.78; H, 9.70. Found: C, 54.80; H,9.66.

EXAMPLE 25

Hydroxy Acetal (−)-32.

A solution of dithiane (+)-30 (3.60 g, 9.12 mmol) in 10% HMPA/THF (60mL) was cooled to −78° C. and treated with t-BuLi (1.7 M in pentane,5.63 mL, 9.58 mmol) dropwise over 15 min. The mixture was stirred 1 h at−78° C. and 1 h at −42° C., then recooled to −78° C. A solution ofbenzyl R-(−)-glycidyl ether (1.65 g, 10.0 mmol) in 10% HMPA/THF (12 mL)was added via cannula. After 0.5 h, the reaction mixture was warmed to−42° C. for 0.5 h and quenched with saturated aqueous NH₄Cl (20 mL). Themixture was diluted with ether (200 mL), washed with water, brine (200mL each), dried over MgSO₄, filtered and concentrated. Flashchromatography (10% ethyl acetate/hexane) afforded (−)-32 (4.04 g, 79%yield) as a colorless oil: [α]²³ _(D) −5.9° © 2.1, CHCl₃); IR (CHCl₃)3450 (w, br), 3020 (m), 2960 (s), 2940 (s), 2910 (m), 2860 (m), 2840(m), 1605 (w), 1500 (w), 1475 (m), 1468 (m), 1458 (m), 1440 (m), 1430(m), 1393 (m), 1387 (m), 1365 (m), 1280 (w), 1255 (m), 1233 (m), 1203(m), 1167 (w), 1153 (w), 1110 (s), 1060 (m), 1045 (m), 1030 (m), 1010(m), 980 (w), 940 (m), 910 (w), 860 (m), 837 (s), 800 (m), 695 (m), 670(m), 660 (m) cm⁻¹; ¹H NMR (500 MHZ, CDCl₃) d 7.35-7.25 (m, 5 H), 4.64(dd, J=4.0, 1.1 Hz, 1 H), 4.57 (ABq, J_(AB)=12.1 Hz, Δδ_(AB)=17.8 Hz, 2H), 4.21 (d, J=7.7 Hz, 1 H), 4.14-4.09 (m, 1 H), 3.48 (dd, J=9.5, 6.0Hz, 1 H), 3.47 (dd, J=9.6, 5.0 Hz, 1 H), 3.37 (d, J=0.7 Hz, 1 H), 3.36(s, 3 H), 3.29 (s, 3 H), 3.08 (ddd, J=14.4, 11.4, 2.9 Hz, 1 H), 2.95(ddd, J=14.4, 11.3, 3.1 Hz, 1 H), 2.71-2.64 (m, 2 H), 2.59 (dqd, J=6.7,6.7, 0.9 Hz, 1 H), 2.49 (dd, J=15.6, 7.9 Hz, 1 H), 2.30 (dq, J=4.0, 7.3Hz, 1 H), 2.27 (dd, J=15.6, 2.3 Hz, 1 H), 2.04-2.00 (m, 1 H), 1.86-1.78(m, 1 H), 1.18 (d, J=7.4 Hz, 3 H), 0.94 (d, J=6.8 Hz, 3 H), 0.90 (s, 9H), 0.08 (s, 3 H), 0.07 (s, 3 H); ¹³C NMR (125 MHZ, CDCl₃) d 138.2,128.4, 127.6, 106.9, 74.4, 73.3, 70.0, 67.9, 55.7, 53.6, 52.6, 47.2,39.4, 38.5, 26.3, 26.1, 26.0, 25.0, 18.3, 9.8, 9.5, −3.9, −4.9; highresolution mass spectrum (FAB, NBA) m/z 581.2763 [(M+Na)⁺; calcd forC₂₈H₅₀O₅S₂SiNa: 581.2767].

EXAMPLE 26

Ketone (+)-33

A solution of hydroxy acetal (−)-32 (3.94 g, 7.05 mmol) in H₂O/MeOH(1:9, 75 mL) was treated with (CF₃CO₂)₂IPh (4.55 g, 10.6 mmol) at 0° C.After 5 min, the mixture was quenched with saturated NaHCO₃ (20 mL) andextracted with ether (200 mL). The organic phase was washed with brine(200 mL), dried over MgSO₄, filtered and concentrated. Flashchromatography (20% ethyl acetate/hexane) furnished (+)-33 (2.66 g, 80%yield) as a colorless oil. [α]²³ _(D) +36° © 0.36, CHCl₃); IR (CHCl₃)3580 (w, br), 3005 (m), 2960 (s), 2930 (s), 2900 (m), 2860 (m), 1710(m), 1463 (m), 1455 (m), 1387 (m), 1362 (m), 1253 (m), 1220 (m), 1105(s), 1070 (s), 1053 (s), 1030 (s), 1002 (m), 938 (m), 866 (m), 830 (s),808 (m), 690 (m), 660 (m) cm⁻¹; ¹H NMR (500 MHZ, CDCl₃) d 7.34-7.25 (m,5 H), 4.54 (apparent s, 2 H), 4.40-4.25 (m, 1 H), 4.23 (dd, J=7.6, 1.9Hz, 1 H), 4.19 (d, J=8.0 Hz, 1 H), 3.46 (dd, J=9.7, 4.9 Hz, 1 H), 3.43(dd, J=9.7, 5.9 Hz, 1 H), 3.27 (s, 3 H), 3.25 (s, 3 H), 3.01 (d, J=3.8Hz, 1 H), 2.76 (dd, J=18.0, 8.7 Hz, 1 H), 2.74 (dq, J=7.1, 7.1 Hz, 1 H),2.62 (dd, J=17.9, 3.2 Hz, 1 H), 1.83 (dqd, J=8.0, 7.0, 1.9 Hz, 1 H),0.97 (d, J=7.1 Hz, 3 H), 0.88 (d, J=6.9 Hz, 3 H), 0.83 (s, 9 H), 0.06(s, 3 H), −0.05 (s, 3 H); ¹³C NMR (125 MHZ, CDCl₃) d 213.0, 138.0,128.4, 127.71, 127.68, 105.0, 73.4, 73.3, 71.8, 66.5, 52.9, 52.6, 52.3,46.5, 37.9, 26.1, 18.4, 12.7, 8.8, −4.1, −4.8; high resolution massspectrum (FAB, NBA) m/z 491.2821 [(M+Na)⁺; calcd for C₂₅H₄₄O₆SiNa:491.2805].

EXAMPLE 27

Diol (−)-34.

A solution of Me₄NBH(OAc)₃ (1.80 g, 6.84 mmol) in HOAc/CH₃CN (1:1, 10.0mL) was cooled to −40° C. and ketone (+)-33 (536 mg, 1.14 mmol) in CH₃CN(5 mL) was added. After 12 h at −20° C., the mixture was treated withsaturated aqueous Rochelle's salt (20 mL) and extracted with CH₂C₂ (3×50mL). The combined organic extracts were washed with saturated NaHCO₃,brine (100 mL each), dried over MgSO₄, filtered and concentrated. Flashchromatography (1:1:1, CH₂Cl₂/ether/hexane) provided (−)-34 (519 mg, 97%yield) as a colorless oil: [α]²³ _(D) −7.78° © 0.900, CHCl₃); IR (CHCl₃)3680 (w), 3460 (m, br), 3015 (m), 2960 (s), 2940 (s), 2900 (m), 2865(s), 1470 (m), 1460 (m),1390 (m), 1365 (m), 1260 (m), 1230 (m), 1208(m), 1112 (s), 1065 (s), 1030 (m), 1010 (m), 942 (m), 865 (m), 838 (m),698 (m) cm⁻¹; ¹H NMR (500 MHZ, CDCl₃) d 7.33-7.30 (m, 4 H), 7.29-7.25(m, 1 H), 4.55 (ABq, J_(AB)=12.0 Hz, Δδ_(AB)=15.7 Hz, 2 H), 4.16-4.11(m, 1 H), 4.13 (d, J=7.8 Hz, 1 H), 4.07 (dd, J=4.8, 1.6 Hz, 1 H), 3.73(br s, 1 H), 3.68 (dddd, J=9.3, 9.3, 2.4, 2.4 Hz, 1H), 3.50 (dd, J=9.6,4.5 Hz, 1 H), 3.42 (dd, J=9.4, 7.0 Hz, 1 H), 3.38 (s, 3 H), 3.29 (s, 3H), 3.09 (d, J=4.0 Hz, 1 H), 1.90 (dqd, J=7.0, 7.0, 1.5 Hz, 1 H), 1.76(br dd, J=13.6, 8.5 Hz, 1 H), 1.68 (dqd, J=9.6, 6.9, 5.0 Hz, 1 H), 1.49(ddd, J=14.3, 9.0, 2.9 Hz, 1 H), 0.894 (d, J=7.9 Hz, 3 H), 0.886 (s, 9H), 0.80 (d, J=7.0 Hz, 3 H), 0.055 (s, 3 H), 0.048 (s, 3 H); ¹³C NMR(125 MHZ, CDCl₃) d 138.2, 128.4, 127.7, 127.6, 107.3, 74.5, 73.3, 71.0,70.9, 67.8, 55.2, 52.1, 45.9, 37.3, 36.9, 25.9, 18.2, 11.6, 10.6, −4.3,−4.7; high resolution mass spectrum (FAB, NBA) m/z 493.2951 [(M+Na)⁺;calcd for C₂₅H₄₆O₆SiNa: 493.2962].

EXAMPLE 28

Alcohol (−)-35.

A solution of (−)-34 (123.3 mg, 0.262 mmol) in benzene (10 mL) wastreated with TsOH.H₂O (2.0 mg, 0.0105 mmol) at room temperature. After20 min, the mixture was quenched with NEt₃ (1.0 mL) and concentrated.Flash chromatography (2% ether/CH₂C₂) afforded 35 (100.1 mg, β/α=2:1,87% yield) as a colorless oil.

β Anomer (35): [α]²³ _(D) −3.3° © 2.25, CHCl₃); IR (CHCl₃) 3680 (w),3580 (w), 3490 (w), 3010 (m), 2960 (s), 2930 (s), 2880 (m), 2860 (s),1603 (w), 1525 (w), 1515 (w), 1493 (m), 1470 (m), 1460 (m), 1450 (m),1387 (m), 1360 (m), 1347 (m), 1330 (m), 1253 (s), 1225 (m), 1200 (m),1143 (m), 1110 (s), 1070 (s), 1045 (s), 1020 (s), 1015 (m), 1003 (m),985 (m), 950 (m), 870 (m), 853 (m), 833 (s), 807 (m), 800 (m), 790 (m),690 (m), 670 (m), 657 (m) cm⁻¹; ¹H NMR (500 MHZ, CDCl₃) d 7.34-7.25 (m,5 H), 4.69 (d, J=2.4 Hz, 1 H), 4.55 (ABq, J_(AB)=12.0 Hz, Δδ_(AB)=14.6Hz, 2 H), 4.17-4.12 (m, 1 H), 3.78 (ddd, J=9.7, 9.7, 2.5 Hz, 1 H), 3.60(apparent t, J=2.7 Hz, 1 H), 3.51 (dd, J=9.5, 4.1 Hz, 1 H), 3.42 (s, 3H), 3.39 (dd, J=9.5, 7.0 Hz, 1 H), 2.86 (d, J=3.8 Hz, 1 H), 1.88(apparent qt, J=7.1, 2.7 Hz, 1 H), 1.76 (ddd, J=14.4, 8.9, 2.6 Hz, 1 H),1.72-1.65 (m, 1 H), 1.53 (ddd, J=14.4, 9.3, 2.9 Hz, 1 H), 0.90 (d, J=8.2Hz, 3 H), 0.89 (s, 9 H), 0.78 (d, J=6.8 Hz, 3 H), 0.04 (s, 3 H), 0.02(s, 3 H); ¹³C NMR (125 MHZ, CDCl₃) d 138.2, 128.4, 127.7, 101.2, 76.7,74.7, 73.3, 73.0, 67.4, 56.6, 41.1, 36.0, 34.7, 25.9, 18.1, 13.7, 9.7,−4.6, −4.9; high resolution mass spectrum (FAB, NBA) m/z 461.2693[(M+Na)⁺; calcd for C₂₄H₄₂O₅SiNa: 461.2699].

α Anomer (35): [α]²³ _(D) +48° © 0.54, CHCl₃); IR (CHCl₃) 3670 (w), 3570(w), 3480 (w, br), 3005 (m), 2960 (s), 2930 (s), 2880 (m), 2855 (s),1600 (w), 1527 (w), 1515 (w), 1495 (w), 1460 (m), 1360 (m), 1253 (s),1225 (m), 1212 (m), 1200 (m), 1170 (m), 1148 (m), 1106 (s), 1087 (s),1048 (s), 1030 (s), 963 (m), 872 (m), 833 (s), 788 (m), 690 (m) cm⁻¹; ¹HNMR (500 MHZ, CDCl₃) d 7.34-7.24 (m, 5 H), 4.55 (ABq, J_(AB)=12.1 Hz,Δδ_(AB)=14.4 Hz, 2 H), 4.30 (d, J=2.9 Hz, 1 H), 4.12-4.07 (m, 1 H), 4.01(ddd, J=9.2, 9.2, 2.7 Hz, 1 H), 3.51 (apparent t, J=4.4 Hz, 1 H), 3.50(dd, J=9.5, 4.2 Hz, 1 H), 3.39 (dd, J=9.5, 7.1 Hz, 1 H), 3.28 (s, 3 H),2.86 (d, J=3.2 Hz, 1 H), 1.85 (qdd, J=7.3, 5.2, 2.9 Hz, 1 H), 1.76 (dqd,J=9.3, 6.9, 4.0 Hz, 1 H), 1.71 (ddd, J=14.5, 9.0, 2.8 Hz, 1 H), 1.55(ddd, J=14.4, 9.2, 2.9 Hz, 1 H), 0.96 (d, J=7.3 Hz, 3 H), 0.88 (s, 9 H),0.81 (d, J=6.8 Hz, 3 H), 0.03 (s, 3 H), −0.01 (s, 3 H); ¹³C NMR d 138.2,128.4, 127.7, 101.2, 76.7, 74.7, 73.3, 73.0, 67.4, 56.7, 41.1, 36.0,34.7, 25.9, 18.1, 13.7, 9.7, −4.6, −4.9; high resolution mass spectrum(FAB, NBA) m/z 461.2715 [(M+Na)⁺; calcd for C₂₄H₄₂O₅SiNa: 461.2699].

EXAMPLE 29

Methyl Pyranoside 36.

A solution of 35 (281.2 mg, β/α=2:1, 0.642 mmol) and 2,6-lutidine (224.0μL, 1.92 mmol) in CH₂Cl₂ (6.0 mL) was cooled to 0° C. and TBSOTf (295.0μL, 1.28 mmol) was added over 5 min. After 1 h at 0° C., the mixturewas-diluted with ethyl acetate (100 mL), washed with aqueous NaHSO₄ (1.0M, 50 mL), brine (100 mL), dried over MgSO₄, filtered and concentrated.Flash chromatography (5% ethyl acetate/hexane) provided 36 (344.6 mg,β/α=2:1, 97% yield) as a colorless oil.

α anomer: [α]²³ _(D) +50.0° © 1.44, CHCl₃); IR (CHCl₃) 2960 (s), 2935(s), 2885 (s), 2860 (s), 1490 (w), 1460 (m), 1388 (m), 1378 (m), 1360(m), 1250 (s), 1190 (m), 1145 (m), 1105 (s), 1085 (s), 1050 (s), 1025(s), 1002 (s), 963 (m), 934 (m), 867 (m), 833 (s), 690 (m) cm⁻¹; ¹H NMR(500 MHZ, CDCl₃) d 7.32-7.25 (m, 5 H), 4.51 (ABq, J_(AB)=12.1 Hz,Δδ_(AB)=19.7 Hz, 2 H), 4.23 (d, J=4.8 Hz, 1 H), 4.03 (dddd, J=8.0, 5.3,5.3, 2.5 Hz, 1 H), 3.87 (ddd, J=9.9, 7.8, 1.8 Hz, 1 H), 3.53 (dd, J=7.2,4.8 Hz, 1 H), 3.39 (dd, J=9.8, 5.6 Hz, 1 H), 3.37 (dd, J=10.0, 5.2 Hz, 1H), 3.33 (s, 3 H), 1.79 (dqd, J=7.1, 7.1, 4.9 Hz, 1 H), 1.71-1.64 (m, 2H), 1.53 (ddd, J=14.4, 8.8, 1.9 Hz, 1 H), 0.94 (d, J=7.0 Hz, 3 H), 0.89(s, 9 H), 0.865 (s, 9 H), 0.862 (d, J=6.9 Hz, 3 H), 0.07 (s, 3 H), 0.04(s, 3 H), 0.03 (s, 3 H), 0.005 (s, 3 H); ¹³C NMR (125 MHZ, CDCl₃) d138.5, 128.3, 127.6, 127.5, 103.8, 75.5, 73.2, 72.8, 69.8, 69.1, 55.7,38.9, 38.5, 37.6, 26.0, 25.8, 18.18, 18.16, 15.1, 12.9, −3.9, −4.6,−4.7, −4.8; high resolution mass spectrum (FAB, NBA) m/z 575.3552[(M+Na)⁺; calcd for C₃₀H₅₆O₅Si₂Na: 575.3564].

β anomer: [α]²³ _(D) +13.3° © 1.38, CHCl₃); IR (CHCl₃) 3003 (m), 2960(s), 2935 (s), 2880 (s), 2860 (s), 1495 (w), 1470 (m), 1464 (m), 1390(m), 1360 (m), 1350 (m), 1330 (w), 1253 (s), 1155 (s), 1140 (s), 1120(s), 1090 (s), 1045 (s), 1022 (s), 1002 (s), 953 (m), 933 (m), 850 (s),830 (s), 690 (m), 658 (m) cm⁻¹; ¹H NMR (500 MHZ, CDCl₃) d 7.32-7.22 (m,5 H), 4.74 (d, J=2.4 Hz, 1 H), 4.50 (ABq, J_(AB)=13.2 Hz, Δδ_(AB)=17.8Hz, 2 H), 4.23-4.18 (m, 1 H), 3.74 (ddd, J=10.6, 10.6, 1.3 Hz, 1 H),3.60 (apparent t, J=2.7 Hz, 1 H), 3.48 (s, 3 H), 3.38 (dd, J=9.8, 4.5Hz, 1 H), 3.35 (dd, J=9.8, 5.7 Hz, 1 H), 1.88 (qdd, J=7.1, 2.7, 2.7 Hz,1 H), 1.66 (ddd, J=14.0, 10.1, 1.6 Hz, 1 H), 1.63-1.55 (m, 1 H), 1.49(ddd, J=14.0, 10.8, 1.8 Hz, 1 H), 0.91 (d, J=7.1 Hz, 3 H), 0.89 (s, 9H), 0.88 (s, 9 H), 0.785 (d, J=6.8 Hz, 3 H), 0.07 (s, 3 H), 0.045 (s, 3H), 0.040 (s, 3 H), 0.02 (s, 3 H); ¹³C NMR (125 MHZ, CDCl₃) d 138.5,128.2, 127.6, 127.4, 100.6, 76.9, 75.8, 73.2, 71.7, 67.9, 56.7, 41.1,38.4, 35.0, 26.1, 25.8, 18.2, 18.1, 14.0, 9.7, −3.9, −4.5, −5.0; highresolution mass spectrum (FAB, NBA) m/z 575.3560 [(M+Na)⁺; calcd forC₃₀H₅₆O₅Si₂Na: 575.3564].

EXAMPLE 30

Primary Alcohol 37.

A solution of 36 (331.6 mg, 0.600 mmol) in EtOH/EtOAc (1:8, 9 mL) wastreated with Pd/C (10% wet, E101 NE/W, 51.2 mg) under H₂ atmosphere for3 h, then filtered and concentrated. Flash chromatography (10% ethylacetate/hexane) provided 37 (276.6 mg, β/α=2:1, 99% yield) as acolorless oil.

β anomer: [α]²³ _(D) +16.9° © 2.52, CHCl₃); IR (CHCl₃) 3680 (w), 3590(w, br), 3450 (w, br), 3000 (m), 2960 (s), 2925 (s), 2880 (m), 2855 (s),1470 (m), 1462 (m), 1388 (m), 1360 (m), 1253 (s), 1222 (m), 1200 (m),1150 (m),1130 (m), 1110 (s), 1098 (m), 1065 (s), 1046 (s), 1023 (s),1002 (m), 980 (m), 952 (m), 894 (m), 865 (m), 850 (m), 830 (s), 663 (m),657 (m) cm⁻¹; ¹H NMR (500 MHZ, CDCl₃) d 4.73 (d, J=2.5 Hz, 1 H),4.09-4.05 (m, 1 H), 3.64 (ddd, J=10.5, 10.5, 1.3 Hz, 1 H), 3.60(apparent t, J=2.5 Hz, 1 H), 3.62-3.59 (m, 1 H), 3.47 (s, 3 H),3.47-3.42 (m, 1 H), 1.95-1.85 (m, 2 H), 1.82 (ddd, J=14.3, 9.2, 1.5 Hz,1 H), 1.60 (dqd, J=10.2, 6.8, 2.5 Hz, 1 H), 1.45 (ddd, J=14.3, 10.7, 2.6Hz, 1 H), 0.895 (d, J=7.5 Hz, 3 H), 0.887 (apparent s, 18 H), 0.785 (d,J=6.8 Hz, 3 H), 0.09 (s, 3 H), 0.08 (s, 3 H), 0.04 (s, 3 H), 0.02 (s, 3H); ¹³C NMR (125 MHZ, CDCl₃) d 100.8, 76.8, 72.2, 69.5, 67.6, 56.8,41.0, 38.2, 34.9, 25.9, 25.8, 18.1, 14.0, 9.7, −4.2, −4.6, −4.7, −5.0;high resolution mass spectrum (FAB, NBA) m/z 485.3080 [(M+Na)⁺; calcdfor C₂₃H₅₀O₅SiNa: 485.3094].

α anomer: [α]²³ _(D) +54.9° © 1.20, CHCl₃); IR (CHCl₃) 3670 (w), 3590(w) 3440 (w, br), 3000 (m), 2960 (s), 2925 (s), 2880 (m), 2855 (s), 1463(m), 1390 (m), 1360 (m), 1255 (s), 1225 (m), 1192 (m), 1168 (m), 1143(m), 1102 (s), 1083 (s),1045 (s), 1030 (m), 1002 (m), 963 (m), 932 (m),862 (m), 833 (s) cm⁻¹; ¹H NMR (500 MHZ, CDCl₃) d 4.25 (d, J=4.2 Hz, 1H), 3.89 (dddd, J=6.5, 4.6, 4.6, 4.6 Hz, 1 H), 3.80 (ddd, J=9.1, 9.1,2.3 Hz, 1 H), 3.61 (br dd, J=10.9, 3.4 Hz, 1 H), 3.51 (dd, J=6.5, 4.6Hz, 1 H), 3.52-3.48 (m, 1 H), 3.33 (s, 3 H), 2.15 (s, br, 1 H), 1.81(dqd, J=6.9, 6.9, 4.2 Hz, 1 H), 1.72-1.60 (m, 3 H), 0.94 (d, J=7.1 Hz, 3H), 0.882 (s, 9 H), 0.879 (s, 9 H), 0.845 (d, J=6.8 Hz, 3 H), 0.09 (s, 3H), 0.08 (s, 3 H), 0.02 (s, 3 H), 0.00 (s, 3 H); ¹³C NMR (125 MHZ,CDCl₃) d 104.0, 72.7, 71.3, 70.0, 67.6, 55.7, 38.7, 38.5, 37.3, 25.8,18.13, 18.08, 15.2, 13.1, −4.4, −4.6, −4.7; high resolution massspectrum (FAB, NBA) m/z 485.3081 [(M+Na)⁺; calcd. for C₂₃H₅₀O₅Si₂Na:485.3094].

EXAMPLE 31

Alcohol 38.

A solution of 37 (276.6 mg, 0.598 mmol) in Et₂O (40 mL) was treated withEtSH (8.90 mL, 120 mmol) and MgBr₂.Et₂O (1.54 g, 5.96 mmol) at roomtemperature. After 60 h, the mixture was diluted with ethyl acetate (50mL), washed with brine (2×100 mL), dried over MgSO₄, filtered andconcentrated. Flash chromatography (3% acetone/hexane) provided 38 α(34.4 mg, 12% yield) and 38 β (211.3 mg, 71% yield).

β anomer: colorless oil; [α]²³ _(D) +16.6° © 1.18, CHCl₃); IR (CHCl₃)3595 (m), 3400 (m, br), 3000 (m), 2960 (s), 2930 (s), 2855 (s), 1655(w), 1612 (s), 1588 (m), 1510 (s), 1462 (s), 1375 (m), 1360 (m), 1300(m), 1250 (s, br), 1170 (m), 1080 (s, br), 1030 (s), 1002 (m), 967 (m),835 (s) cm⁻¹; ¹H NMR (500 MHZ, CDCl₃) d 5.08 (d, J=2.3 Hz, 1 H),4.04-4.00 (m, 1H), 3.62 (ddd, J=10.4, 10.4, 1.0 Hz, 1 H), 3.60 (ddd,J=11.1, 11.1, 4.2 Hz, 1 H), 3.56 (apparent t, J=2.7 Hz, 1 H), 3.43 (ddd,J=11.7, 7.9, 4.1 Hz, 1 H), 2.70 (dq, J=12.7, 7.4 Hz, 1 H), 2.67 (dq,J=12.8, 7.5 Hz, 1 H), 1.95 (dd, J=7.9, 4.8 Hz, 1 H), 1.86 (qdd, J=7.1,2.7, 2.7 Hz, 1 H), 1.79 (ddd, J=14.4, 9.0, 1.4 Hz, 1 H), 1.66-1.59 (m, 1H), 1.5.7 (s, 3 H), 1.45 (ddd, J=14.4, 10.5, 2.7 Hz, 1 H), 1.27(apparent t, J=7.4 Hz, 1 H), 0.99 (d, J=7.1 Hz, 3 H), 0.90 (s, 9 H),0.89 (s, 9 H), 0.79 (d, J=6.8 Hz, 3 H), 0.083 (s, 3 H), 0.075 (s, 3 H),0.04 (s, 3 H), 0.03 (s, 3 H); ¹³C NMR (125 MHZ, CDCl₃) d 81.0, 76.2,75.0, 69.8, 67.6, 41.9, 38.3, 34.5, 25.9, 25.8, 25.2, 18.1, 15.2, 14.4,11.5, −4.2, −4.56, −4.63, −4.9; high resolution mass spectrum (FAB, NBA)m/z 515.3037 [(M+Na); calcd for C₂₄H₅₂O₄SSi₂Na: 515.3023].

α anomer: colorless oil; [α]²³ _(D) +94.5° © 0.33, CHCl₃); IR (CHCl₃)3680 (w), 3580 (w), 3440 (w, br), 3010 (m), 2960 (s), 2930 (s), 2880(m), 2860 (s), 1513 (w), 1470 (m), 1462 (m), 1390 (m), 1380 (m), 1360(m), 1257 (s), 1225 (m), 1200 (m), 1114 (m), 1070 (s), 1047 (s), 1022(m), 1002 (m), 957 (m), 860 (m), 833 (s), 705 (s), 660 (m) cm⁻¹; ¹H NMR(500 MHZ, CDCl₃) d 4.76 (d, J=3.1 Hz, 1 H), 4.04 (ddd, J=9.8, 9.8, 1.8Hz, 1 H), 3.84 (dddd, J=5.0, 5.0, 5.0, 5.0 Hz, 1 H), 3.57 (dd, J=11.0,4.2 Hz, 1 H), 3.53 (apparent t, J=4.0 Hz, 1 H), 3.47 dd, J=11.0, 4.7 Hz,1 H), 2.57 (dq, J=12.8, 7.5 Hz, 1 H), 2.54 (dq, J=12.8, 7.5 Hz, 1 H),1.97-1.91 (m, 1 H), 1.75 (ddd, J=14.7, 6.1 Hz, 2.0, 1 H), 1.72-1.65 (m,1 H), 1.60 (ddd, J=14.9, 10.0, 5.1 Hz, 1 H), 1.60-1.50 (br, 1 H), 1.23(apparent t, J=7.4 Hz, 3 H), 1.06 (d, J=7.1 Hz, 3 H), 0.92 (s, 9 H),0.89 (s, 9 H), 0.85 (d, J=6.9 Hz, 3 H), 0.12 (s, 3 H), 0.08 (s, 3 H),0.05 (s, 3 H), 0.02 (s, 3 H); ¹³C NMR (125 MHZ, CDCl₃) d 85.3, 73.8,71.5, 69.2, 67.5, 40.6, 38.2, 36.4, 26.4, 26.1, 25.9, 18.2, 18.1, 17.5,14.7, 13.9, −4.2, −4.4, −4.8; high resolution mass spectrum (FAB, NBA)m/z 515.3045 [(M+Na)⁺; calcd for C₂₄H₅₂O₄SSi₂Na: 515.3023].

EXAMPLE 32

Fragment (+)-C.

A solution of DMSO (100 μL, 1.42 mmol) in CH₂Cl₂ (2.0 mL) was cooled to−78° C. and oxalyl chloride (55.0 μl, 0.630 mmol) was introduceddropwise. After 15 min. a cooled (−78° C.) solution of 38 α (104.8 mg,0.213 mmol) in CH₂Cl₂ (1.0 mL) was introduced via cannula (2×500 μLrinse). The resultant milky solution was stirred for 15 min at −78° C.and I-Pr₂NEt (370 μl, 2.12 mmol) was added dropwise. The reactionmixture was stirred for 0.5 h, slowly warmed to room temperature (15min), and quenched with aqueous NaHSO₄ (1.0 M, 4.0 mL). The organicphase was diluted with ether (30 mL), washed with brine (3×30 mL), driedover MgSO₄, filtered and concentrated. Flash chromatography (2% ethylacetate/hexane) furnished (+)-C (88.8 mg, 86% yield) as a colorless oil:[α]²³ _(D) +11.2° © 1.42, CHCl₃); IR (CHCl₃) 2960 (s), 2935 (s), 2880(s), 2860 (s), 1735 (s), 1470 (m), 1460 (m), 1380 (m), 1360 (m), 1320(m), 1295 (w), 1265 (s), 1153 (m), 1120 (m), 1080 (m), 1060 (s), 1043(s), 1025 (s), 1003 (s), 970 (m), 950 (m), 935 (m), 903 (m), 865 (m),835 (s), 800 (m), 690 (m) cm⁻¹; ¹H NMR (500 MHZ, CDCl₃) d 9.56 (d, J=0.9Hz, 1 H), 5.07 (d, J=2.3 Hz, 1 H), 4.35 (ddd, J=7.9, 2.2, 0.6 Hz, 1 H),3.70 (ddd, J=10.3, 10.3, 1.5 Hz, 1 H), 3.57 (apparent t, J=2.7 Hz, 1 H),2.71-2.60 (m, 2 H), 1.86 (apparent qt, J=7.1, 2.7 Hz, 1H), 1.78 (ddd,J=14.1, 10.4, 7.8 Hz, 1 H), 1.72-1.66 (m, 1 H), 1.67 (ddd, J=10.3, 3.9,1.8 Hz, 1 H), 1.25 (apparent t, J=7.4 Hz, 3 H), 1.00 (d, J=7.2 Hz, 3 H),0.90 (s, 9 H), 0.89 (s, 9 H), 0.78 (d, J=6.8 Hz, 3 H), 0.10 (s, 3 H),0.04 (s, 6 H), 0.03 (s, 3 H); ¹³C NMR (125 MHZ, CDCl₃) d 202.6, 81.2,76.1, 74.9, 73.7, 41.9, 35.8, 34.4, 25.82, 25.79, 25.2, 18.2, 18.1,15.3, 14.3, 11.5, −4.2, −4.5, −4.9, −5.2; high resolution mass spectrum(CI, NH₃) m/z 491.3058 [(M+H)⁺; calcd for C₂₄H₅₁O₄SSi₂: 491.3046].

EXAMPLE 33

Fragment (−)-B.

From vinyl bromide (−)-22: A solution of (−)-22 (3.78 g, 8.04 mmol) inHMPA/DMF (2:1, 6 mL) was added to a mixture of KI (4.15 g, 250 mmol),NiBr₂ (34.9 mg, 0.160 mmol), and Zn powder (23.2 mg, 0.355 mmol). Themixture was stirred at room temperature for 15 min then heated to 90° C.The green color mixture turned black-brown after 5 min and dark greenafter 1 h. After additional 1 h at 90° C., the mixture was cooled toroom temperature, diluted with ethyl acetate (200 mL), washed with brine(4×200 mL), dried over MgSO₄, filtered and concentrated. Flashchromatography (2% ethyl acetate/hexane) provided B (3.59 g, containing13% unreacted vinyl bromide) as a colorless oil.

From aldehyde (+)-18: A suspension of EtPh₃P⁺I⁻ (15.1 g, 36.1 mmol) inTHF (200 mL) was treated with n-BuLi (1.6 M in hexane, 23.0 mL, 36.8mmol) at room temperature over 10 min. After an additional 10 min, theresultant red solution was added via cannula to a cooled (−78° C.)solution of I₂ (8.02 g, 31.6 mmol) in THF (300 mL) over 15 min. Theyellow slurry formed was stirred at −78° C. for 5 min and at −23° C. for10 min. NaHMDS (1.0 M in THF, 31.0 mL, 31.0 mmol) was added over 8 minand the mixture stirred 15 min further. A solution of aldehyde (+)-18(6.96 g, 18.3 mmol) in THF (50 mL) was introduced via cannula (10 mLrinse), and the reaction mixture was stirred at −23° C. for 10 min,warmed to room temperature, stirred for 3 h, and then quenched with MeOH(10 mL). Following concentration and filtration through a silica column(50% ethyl acetate/hexane), the filtrate was washed with saturatedaqueous Na₂S₂O₃, brine (300 mL each), dried over MgSO₄, filtered andconcentrated. Flash chromatography (5% ethyl acetate/hexane) furnished B(6:1 Z/E, 3.94 g, 41% yield) as a colorless oil.

An analytical sample of (−)-B was obtained by reversed-phase HPLC(gradient elution, 90% CH₃CN/H₂O→100% CH₃CN): [α]²³ _(D) −23° © 0.30,CHCl₃); IR (CHCl₃) 3000 (m), 2960 (s), 2930 (s), 2880 (m), 2855 (s),1610 (m), 1588 (w), 1510 (s), 1463 (m), 1453 (m), 1428 (m), 1405 (w),1390 (m), 1377 (m), 1360 (m), 1303 (m), 1250 (s), 1180 (m), 1172 (m),1080 (s, br), 1033 (s), 1002 (m), 948 (m), 935 (m), 922 (m), 833 (s),803 (m), 760 (m, br), 720 (m), 658 (m) cm⁻¹; ¹H NMR (500 MHZ, CDCl₃) d7.25 (d, J=8.6 Hz, 2 H), 6.87 (d, J=8.7 Hz, 2 H), 5.28 (apparent dd,J=8.9, 1.4 Hz, 1 H), 4.41 (ABq, J_(AB)=7.0 Hz, Δδ_(AB)=10.2 Hz, 2 H),3.80 (s, 3 H), 3.60 (apparent t, J=5.3 Hz, 1 H), 3.51 (dd, J=9.1, 5.1Hz, 1 H), 3.23 (dd, J=9.0, 8.0 Hz, 1 H), 2.54-2.47 (m, 1 H), 2.44 (d,J=1.4 Hz, 3 H), 2.00-1.92 (m, 1 H), 1.00 (d, J=6.9 Hz, 3 H), 0.95 (d,J=6.7 Hz, 3 H), 0.89 (s, 9 H), 0.02 (s, 3 H), 0.01. (s, 3 H); ¹³C NMR(125 MHZ, CDCl₃) d 159.1, 139.6, 131.0, 129.1, 113.7, 98.9, 76.5, 72.6,72.5, 55.3, 44.5, 38.7, 33.5, 26.1, 18.4, 14.7, 14.5, −3.95, −3.99; highresolution mass spectrum (FAB, NBA) m/z 541.1626 [(M+Na)⁺; calcd forC₂₃H₃₉O₃ISiNa: 541.1611].

EXAMPLE 34

Olefin (−)-39.

ZnCl₂ (1.32 g, 9.69 mmol) was dried at 160° C. under vacuum overnightand then treated with a solution of (−)- A (5.25 g, 9.59 mmol) in dryEt₂O (50 mL) via a cannula (2×25 mL rinse). The mixture was stirred atroom temperature until most of the ZnCl₂ dissolved and cooled to −78° C.t-BuLi (1.7 M in pentane, 17.0 mL) was added over 30 min, and theresultant solution was stirred 15 min further, warmed to roomtemperature, and stirred for 1 h. The solution was added by cannula to amixture of B (3.21 g, 6.19 mmol; 6:1 Z/E) and Pd(PPh₃)₄ (364.0 mg, 0.315mmol). The mixture was covered with aluminum foil, stirred overnight,and then diluted with ethyl acetate (100 ML), washed with brine (2×100mL), dried over MgSO₄, filtered and concentrated. Flash chromatography(5% ethyl acetate/hexane) gave (−)-39 (3.32 g, 66% yield) as a whitesemisolid: [α]²³ _(D) −28.6° © 1.53, CHCl₃); IR (CHCl₃) 3010 (m), 2970(s), 2940 (s), 2865 (s), 1620 (m), 1590 (w), 1520 (s), 1465 (s), 1445(m), 1390 (m), 1380 (m), 1360 (m), 1305 (m), 1250 (s), 1175 (m), 1115(s), 1080 (s), 1040 (s), 970 (m), 940 (w), 860 (m), 835 (s) cm⁻¹; ¹H NMR(500 MHZ, CDCl₃) d 7.36 (d, J=8.7 Hz, 2 H), 7.22 (d, J=8.6 Hz, 2 H),6.86 (d, J=9.0 Hz, 2 H), 6.84 (d, J=8.9 Hz, 2 H), 5.37 (s, 1 H), 5.00(d, J=10.2 Hz, 1 H), 4.36 (ABq, J_(AB)=11.6 Hz, Δδ_(AB)=17.4 Hz, 2 H),4.08 (dd, J=11.2, 4.7 Hz, 1 H), 3.78 (s, 3 H), 3.77 (s, 3 H), 3.61 (dd,J=7.1, 1.8 Hz, 1 H), 3.51 (dd, J=9.9, 1.7 Hz, 1 H), 3.47 (apparent t,J=11.0 Hz, 1 H), 3.46 (dd, J=9.1, 5.0 Hz, 1 H), 3.38 (dd, J=6.0, 4.8 Hz,1 H), 3.19 (apparent t, J=8.8 Hz, 1 H), 2.51 (ddq, J=10.1, 6.5, 6.5 Hz,1 H), 2.32 (apparent t, J=12.2 Hz, 1 H), 2.08-2.02 (m, 1 H), 1.99-1.93(m, 2 H), 1.88 (dqd, J=7.1, 7.1, 1.8 Hz, 1 H), 1.67 (br d, J=11.1 Hz, 1H), 1.55 (d, J=0.5 Hz, 3 H), 1.01 (d, J=7.1 Hz, 3 H), 0.94 (d, J=6.9 Hz,3 H), 0.90 (s, 9 H), 0.89 (d, J=6.7 Hz, 3 H), 0.87 (s, 9 H), 0.74 (d,J=6.3 Hz, 3 H), 0.73 (d, J=6.4 Hz, 3 H), 0.03 (s, 3 H), 0.013 (s, 3 H),0.008 (s, 3 H), 0.003 (s, 3 H); ¹³C NMR (125 MHZ, CDCl₃) d 159.8, 159.0,132.0, 131.5, 131.2, 131.1, 129.0, 127.3, 113.7, 113.5, 101.1, 83.4,78.49, 78.46, 73.3, 72.6, 72.5, 55.3, 38.8, 38.2, 37.5, 35.6, 33.7,30.8, 26.27, 26.25, 23.1, 18.42, 18.40, 17.0, 14.6, 12.6, 12.1, 10.9,−3.5, −3.7, −3.8, −3.9; high resolution mass spectrum (FAB, NBA) m/z835.5315 [(M+Na)⁺; calcd for C₄₇H₈₀O₇Si₂Na: 835.5341].

Anal. Calcd for C₄₇H₈₀O₇Si₂: C, 69.41; H, 9.91. Found: C, 69.52; H,10.10.

EXAMPLE 35

Alcohol (−) -40.

A solution of olefin (−)-39 (2.65 g, 3.26 mmol) in CH₂Cl₂ (32 mL) wascooled to 0° C. and treated with H₂O (1.50 mL) and DDQ (774 mg, 3.41mmol). After 4 h, the mixture was diluted with CH₂Cl₂ (20 mL), driedover MgSO₄, and filtered through a silica column (50% ethylacetate/hexane). Following concentration, the residue was dissolved inEtOH (50 mL) and treated with NaBH₄ (500 mg, excess) at room temperatureto reduce the contaminated p-methoxybenzyl aldehyde. After 0.5 h, themixture was quenched with saturated aqueous NH₄Cl (50 mL) at 0° C. thenconcentrated. The residue was partitioned between CH₂Cl₂ (200 mL) andwater (100 mL). The organic phase was washed with water (100 mL), driedover MgSO₄, filtered and concentrated. Flash chromatography (10% ethylacetate/hexane) provided (−)-40 (2.06 g, 91% yield) as a white solid. mp99-100° C.; [α]²³ _(D) −25.4° © 1.35, CHCl₃); IR (CHCl₃) 3520 (w), 3010(m), 2960 (s), 2940 (s), 2880 (m), 2860 (m), 1620 (m), 1593 (w), 1520(m), 1565 (m), 1390 (m), 1360 (m), 1255 (s), 1175 (m), 1165 (m), 1117(m), 1075 (s), 1037 (s), 1025 (s), 1005 (m), 982 (m), 965 (m), 930 (w),835 (s), 800 (m), 705 (w), 675 (w), 660 (w) cm⁻¹; ¹H NMR (500 MHZ,CDCl₃) d 7.36 (d, J=8.7 Hz, 2 H), 6.86 (d, J=8.8 Hz, 2 H), 5.37 (s, 1H), 5.01 (d, J=10.1 Hz, 1 H), 4.09 (dd, J=11.2, 4.7 Hz, 1 H), 3.79 (s, 3H), 3.65 (dd, J=10.4, 4.7 Hz, 1 H), 3.63 (dd, J=7.0, 1.8 Hz, 1 H),3.54-3.50 (m, 1 H), 3.51 (dd, J=10.0, 2.0 Hz, 1 H), 3.47 (apparent t,J=11.2 Hz, 1 H), 3.41 (dd, J=6.6, 4.0 Hz, 1 H), 2.59 (ddq, J=13.2, 6.7,6.7 Hz, 1 H), 2.33 (apparent t, J=12.2 Hz, 1 H), 2.24 (apparent t, J=5.5Hz, 1 H), 2.09-1.95 (m, 2 H), 1.89 (dqd, J=7.0, 7.0, 1.7 Hz, 1 H),1.84-1.77 (m, 1 H), 1.72 (br d J=11.0 Hz, 1 H), 1.58 (d, J=0.8 Hz, 3 H),1.01 (d, J=7.1 Hz, 3 H), 0.98 (d, J=7.1 Hz, 3 H), 0.94 (d, J=6.7 Hz, 3H), 0.910 (s, 9 H), 0.905 (s, 9 H), 0.75 (d, J=7.1 Hz, 3 H), 0.74 (d,J=7.1 Hz, 3 H), 0.09 (s, 3 H), 0.07 (s, 3 H), 0.05 (s, 3 H), 0.01 (s, 3H); ¹³C NMR (125 MHZ, CDCl₃) d 159.8, 133.0, 131.5, 130.5, 127.3, 113.4,101.0, 83.3, 81.6, 78.4, 73.3, 65.4, 55.3, 38.5, 38.2, 37.6, 37.0, 33.7,30.8, 26.17, 26.16, 23.2, 18.4, 18.3, 17.4, 15.7, 12.6, 12.1, 10.9,−3.57, −3.61, −3.66, −3.9; high resolution mass spectrum: (CI, NH₃) m/z693.4918 [(M+H)⁺; calcd for C₃₉H₇₃O₆Si₂: 693.4945].

Anal. Calcd for C₃₉H₇₂O₆Si₂: C, 67.58; H, 10.47. Found: C, 67.30; H,10.54.

EXAMPLE 36

Phosphonium Salt (−)-49.

A solution of alcohol (−)-40 (402.8 mg, 0.577 mmol) in PhH/Et₂O (1:2, 45mL) was treated with PPh₃ (532 mg, 2.03 mmol) and imidazole (158 mg,2.32 mmol). After the imidazole dissolved, I₂ (437 mg, 1.72 mmol) wasadded under vigorous stirring. The mixture was stirred 2 h and thentreated with NEt₃ (2 mL). The resultant yellow suspension was dilutedwith CH₂Cl₂ (50 mL) and washed with saturated aqueous Na₂S₂O₃ (100 mL),saturated aqueous NaHCO₃(100 mL), and brine (2×100 mL). The organicphase was dried over MgSO₄, filtered and concentrated. Filtrationthrough a short silica column (NEt₃/ethyl acetate/hexane, 2:10:90)removed triphenylphosphine oxide, affording the impure iodide 42.Preparative TLC (500 mm silica gel plate, 4% acetone/hexane) furnishedan analytical sample as an unstable white solid: ¹H NMR (500 MHZ, CDCl₃)d 7.35 (d, J=8.8 Hz, 2 H), 6.85 (d, J=8.7 Hz, 2 H), 5.37 (s, 1 H), 5.02(d, J=10.2 Hz, 1 H), 4.08 (dd, J=11.2, 4.7 Hz, 1 H), 3.78 (s, 3 H), 3.62(dd, J=7.0, 1.8 Hz, 1 H), 3.51 (dd, J=9.9, 1.7 Hz, 1 H), 3.47 (apparentt, J=11.1 Hz, 1 H), 3.37 (dd, J=6.3, 4.3 Hz, 1 H), 3.32 (dd, J=9.6, 4.5Hz, 1 H), 2.99 (dd, J=9.5, 8.6 Hz, 1 H), 2.50 (ddq, J=10.2, 6.5, 6.5 Hz,1 H), 2.31 (apparent t, J=12.2 Hz, 1 H), 2.08-1.95 (m, 2 H), 1.88 (dqd,J=7.1, 7.1, 1.7 Hz, 1 H), 1.85-1.78 (m, 1 H), 1.74 (br d, J=11.7 Hz, 1H), 1.57 (apparent s, 3 H), 1.01 (apparent d, J=7.0 Hz, 6 H), 0.91-0.89(m, 3 H), 0.90 (s, 9 H), 0.89 (s, 9 H), 0.74 (d, J=6.8 Hz, 3 H), 0.73(d, J=6.7 Hz, 3 H), 0.06 (s, 3 H), 0.05 (s, 3 H), 0.01 (s, 3 H), −0.02(s, 3 H); ¹³C NMR (125 MHZ, CDCl₃/1% pyridine-d₅, 20 mg sample) d 159.8,132.9, 131.5, 130.4, 127.3, 113.5, 101.1, 83.3, 79.6, 78.5, 73.3, 55.3,41.4, 38.3, 37.6, 36.0, 33.7, 30.8, 26.20, 26.17, 23.2, 18.4; 17.7,17.3, 13.5, 12.6, 12.2, 10.9, −3.5, −3.6, −4.0; high resolution massspectrum (FAB, NBA) m/z 803.3935 [(M+H)⁺; calcd for C₃₉H₇₂O₅ISi₂:803.3963].

The very sensitive impure iodide (obtained by filtration through silica)was quickly mixed with I-Pr₂NEt (300 μL, 1.72 mmol) and PPh₃ (2.47 g,9.42 mmol). The mixture was heated at 80° C. for 24 h, then cooled toroom temperature and extracted with hexane (2×30 mL). The residue waspurified by flash chromatography (2% MeOH/CHCl₃) furnishing (−)-49(224.9 mg, 37% yield from (−)-39) as a pale yellow foam. The hexaneextract was concentrated and purified by flash chromatography (2% ethylacetate/hexane) affording a mixture of cyclization products (200 mg).Further purification by normal phase HPLC (1.5% ethyl acetate/hexane)provided (−)-50 as the major cyclization product.

Wittig reagent (−)-49: [α]²³ _(D) −25.3° © 1.48, CHCl₃); IR (CHCl₃) 2960(s), 2930 (s), 2860 (m), 1615 (m), 1590 (w), 1515 (m), 1485 (w), 1460(m), 1440 (m), 1385 (m), 1360 (m), 1300 (m), 1250 (s), 1215 (m, br),1180 (m), 1110 (s), 1080 (m), 1025 (m), 1005 (m), 965 (m), 945 (w), 860(m), 830 (s), 732 (m), 725 (m), 710 (m), 680 (m), 653 (m) cm⁻¹; ¹H NMR(500 MHZ, CDCl₃; concentration dependent) d 7.82-7.76 (m, 15 H), 7.35(d, J=8.8 Hz, 2 H), 6.84 (d, J=8.8 Hz, 2 H), 5.35 (s, 1 H), 5.30 (d,J=10.5 Hz, 1 H), 4.07 (dd, J=11.2, 4.7 Hz, 1 H), 3.77 (s, 3 H),3.73-3.67 (m, 2 H), 3.56 (dd, J=7.0, 1.8 Hz, 1 H), 3.48 (dd, J=9.8, 1.7Hz, 1 H), 3.46 (apparent t, J=11.1 Hz, 1 H), 3.31 (ddd, J=15.6, 11.2,11.2 Hz, 1 H), 2.49 (ddq, J=10.5, 6.4, 6.4 Hz, 1 H), 2.25 (apparent t,J=12.1 Hz, 1 H), 2.10-1.92 (m, 3 H), 1.85 (dqd, J=7.1, 7.1, 1.8 Hz, 1H), 1.57-1.52 (m, 1 H), 1.56 (s, 3 H), 0.98 (d, J=7.1 Hz, 3 H), 0.89 (d,J=6.6 Hz, 3 H), 0.852 (s, 9 H), 0.849 (s, 9 H), 0.72-0.71 (m, 3 H), 0.71(d, J=6.6 Hz, 3 H), 0.69 (d, J=6.9 Hz, 3 H), 0.10 (s, 3 H), −0.02 (s, 3H), −0.03 (s, 3 H), −0.07 (s, 3 H); ¹³C NMR (125 MHZ, CDCl₃) d 159.8,135.2 (J_(CP)=2.6 Hz), 133.5 (J_(CP)=10.0 Hz), 132.9, 131.4, 130.6(J_(CP)=12.6 Hz), 130.3, 127.3, 118.4 (J_(CP)=85.5 Hz), 113.4, 101.0,83.2, 80.1 (J_(CP)=14.0 Hz), 78.3, 73.2, 55.3, 38.1, 37.4, 36.0, 33.7(J_(CP)=4.4 Hz), 33.6, 30.7, 26.1, 25.5 (J_(CP)=49.7 Hz), 22.9, 18.33,18.29, 17.2, 17.1, 12.5, 12.1, 10.9, −3.2, −3.6, −3.7, −4.0; highresolution mass spectrum (FAB, NBA) m/z 937.5708 [(M−I)⁺; calcd forC₅₇H₈₆O₅PSi₂: 937.5751].

Olefin (−)50: white solid; mp 80-82° C.; [α]²³ _(D) −18° © 0.48, CHCl₃);IR (CHCl₃) 2955 (s), 2920 (s), 2880 (m), 2850 (s), 1640 (w), 1613 (m),1588 (w), 1517 (m), 1460 (m), 1387 (m), 1360 (m),1300 (m), 1250 (s),1178 (m), 1170 (m), 1160 (m), 1115 (m), 1080 (m), 1023 (s), 1000 (m),980 (m), 960 (m), 930 (w), 887 (m), 855 (m), 830 (m), 715 (m) cm⁻¹; ¹HNMR (500 MHZ, C₆D₆) d 7.62 (d, J=8.7 Hz, 2 H), 6.83 (d, J=8.7 Hz, 2 H),5.46 (s, 1 H), 5.00 (s, 1 H), 4.95 (s, 1 H), 3.93 (dd, J=11.1, 4.7 Hz, 1H), 3.89 (dd, J=7.2, 1.5 Hz, 1 H), 3.55 (dd, J=9.9, 1.9 Hz, 1 H), 3.51(apparent t, J=5.9 Hz, 1 H), 3.27 (s, 3 H), 3.22 (apparent t, J=11.0 Hz,1 H), 2.32 (dd, J=13.6, 3.5 Hz, 1 H), 2.27-2.20 (m, 1 H), 2.16 (dd,J=13.7, 9.5 Hz, 1 H), 2.07-1.92 (m, 4 H), 1.87-1.80 (m, 1 H), 1.50-1.42(m, 1 H), 1.18 (d, J=7.1 Hz, 3 H), 1.10 (d, J=6.6 Hz, 3 H), 1.06 (d,J=6.6 Hz, 3 H), 1.04 (s, 9 H), 1.02 (d, J=7.0 Hz, 3 H), 1.00 (s, 9 H),0.41 (d, J=6.7 Hz, 3 H), 0.13 (s, 3 H), 0.09 (s, 3 H), 0.08 (s, 3 H),0.06 (s, 3 H); ¹³C NMR (125 MHZ, CDCl₃) d 159.8 (q), 150.7 (q), 131.5(q), 127.3, 113.4, 108.3 (CH₂), 101.0, 83.2, 81.9, 78.1, 73.3 (CH₂),55.2, 49.9, 44.9, 41.4 (CH₂), 39.0 (CH₂), 38.3, 36.6, 33.4, 30.8, 26.3,25.9, 18.5 (q), 18.2 (q), 17.8, 15.5, 12.9, 12.1, 11.0, −3.4, −3.7,−4.6, −4.7; high resolution mass spectrum (FAB, NBA) m/z 697.4642[(M+Na)⁺; calcd for C₃₉H₇₀O₅Si₂Na: 697.4659].

EXAMPLE 37

Model Olefin (+)-43.

NaHMDS (0.6 M in PhMe, 9.46 mL, 5.68 mmol) was added over 10 min to asuspension of (CH₃)₂CHP⁺Ph₃ I⁻ (2.52 g, 5.83 mmol) in PhMe (20 mL) atroom temperature. After 15 min, the mixture was cooled to −78° C., andaldehyde (+)-18 (1.46 g, 3.84 mmol) in PhMe (15 mL) was introduced via acannula (15 mL rinse). After 20 min at −78° C. and 30 min at roomtemperature, the reaction was quenched with MeOH (1.0 mL). The solutionwas separated, and the oil residue was extracted with hexane (3×30 mL).The combined organic solutions were then concentrated and, and flashchromatography (2% ethyl acetate/hexane) provided (+)-43 (1.44 g, 92%yield) as a colorless oil: [α]²³ _(D) +8.07° © 2.57, CHCl₃); IR (CHCl₃)2960 (s), 2925 (s), 2880 (s), 2855 (s), 1610 (m), 1585 (m), 1510 (s),1460 (s), 1375 (m), 1360 (m), 1300 (m), 1245 (s), 1172 (m), 1085 (s,br), 1035 (s), 1003 (m), 970 (m), 950 (m), 935 (m), 862 (s), 835 (s)cm⁻¹; ¹H NMR (500 MHZ, CDCl₃) d 7.23 (d, J=9.0 Hz, 2 H), 6.85 (d, J=8.6Hz, 2 H), 4.92 (d-quintet, J=9.7, 1.4 Hz, 1 H), 4.37 (apparent s, 2 H),3.78 (s, 3 H), 3.49 (dd, J=9.2, 4.9 Hz, 1 H), 3.39 (dd, J=6.3, 4.5 Hz, 1H), 3.19 (dd, J=9.0, 8.4 Hz, 1 H), 2.49 (ddq, J=9.6, 6.7, 6.7 Hz, 1 H),2.00-1.92 (m, 1 H), 1.63 (d, J=1.2 Hz, 3 H), 1.55 (d, J=-1.3 Hz, 3 H),0.945 (d, J=7.0 Hz, 3 H), 0.874 (d, J=6.7 Hz, 3 H), 0.873 (s, 9 H), 0.01(apparent s, 6 H); ¹³C NMR (125 MHZ, CDCl₃) 159.0, 131.1, 129.7, 129.4,129.1, 113.7, 78.6, 72.6, 55.3, 38.5, 36.0, 26.2, 25.8, 18.4, 17.9,17.0, 14.8, −3.88, −3.95; high resolution mass spectrum (CI, NH₃) m/z407.2984 [(M+H)⁺; calcd for C₂₄H₄₃O₃Si: 407.2981].

EXAMPLE 38

Alcohol (+)-44.

A mixture of olefin (+)-43 (387.6 mg, 0.954 mmol) in CH₂Cl₂ (10 mL) wastreated with H₂O (500 μL) and DDQ (320 mg, 1.41 mmol). After 30 min atroom temperature, the mixture was filtered through a short silica plug(50% ethyl acetate/hexane) and concentrated. Flash chromatography (3%ethyl acetate/hexane) provided (+)-43 (273.1 mg, 99% yield) as acolorless oil: [α]²³ _(D) +17.5° © 2.80, CHCl₃); IR (CHCl₃) 3620 (w),3500 (m, br), 2955 (s), 2925 (s), 2880 (s), 2860 (s), 1460 (s), 1405(m), 1375 (m), 1360 (m), 1337 (m), 1252 (s), 1070 (s), 1050 (s), 1015(s), 1002 (s), 978 (m), 933 (m), 832 (s) cm⁻¹; ¹H NMR (500 MHZ, CDCl₃) d4.92 (apparent d quintet, J=9.7, 1.4 Hz, 1 H), 3.66 (ddd, J=11.0, 4.4,4.4 Hz, 1 H), 3.52 (ddd, J=11.0, 5.5, 5.5 Hz, 1 H), 3.42 (dd, J=6.8, 4.0Hz, 1 H), 2.57 (ddq, J=9.6, 6.8, 6.8 Hz, 1 H), 2.45 (apparent t, J=5.2Hz, 1 H), 1.85-1.78 (m, 1 H), 1.65 (d, J=1.3 Hz, 3 H), 1.59 (d, J=1.3Hz, 3 H), 0.98 (d, J=7.1 Hz, 3 H), 0.92 (d, J=6.8 Hz, 3 H), 0.90 (s, 9H), 0.08 (s, 3 H), 0.05 (s, 3 H); ¹³C NMR (125 MHZ, CDCl₃) d 130.7,128.5, 81.7, 65.5, 38.1, 37.4, 26.2, 25.8, 18.3, 17.9, 17.4, 15.9, −3.7,−3.9; high resolution mass spectrum (CI, NH₃) m/z 287.2418 [(M+H)⁺;calcd for C₁₆H₃₅O₂Si: 287.2406].

EXAMPLE 39

Wittig Reagent (+)-46.

Iodine (1.08 g, 4.24 mmol) was added to a solution of alcohol (+)-44(810 mg, 2.83 mmol), PPh₃ (1.11 g, 4.24 mmol) and imidazole (289 mg,4.24 mmol) in benzene/ether (1:2, 21 mL) under vigorous stirring at roomtemperature. After 40 min, the mixture was diluted with ether (100 mL),washed with saturated Na₂S₂O₃ (50 mL), brine (100 mL), dried over MgSO₄,filtered and concentrated. Flash chromatography (hexane) provided amixture of 45/47/48 (1.06 g, 97% yield, 18:1:1) as a colorless oil; Thismaterial was then treated with I-Pr₂NEt (928 μL, 5.33 mmol) and PPh₃(7.01 g, 26.7 mmol) then heated at 80° C. for 13 h. The mixture wasextracted with hexane. (3×100 mL). The residue was purified by flashchromatography (2% MeOH/CHCl₃) providing Wittig reagent (+)-48 (207.1mg, 38% yield from (+)-46) as a pale yellow foam. The hexane extract wasconcentrated and purified by flash chromatography (hexane) affording amixture of two cyclization products (380 mg) and further purification bypreparative TLC (hexane) afforded (−)-49 and (−)-50.

Wittig reagent (+)-46: [α]²³ _(D) +4.8° © 1.23, CHCl₃); IR (CHCl₃) 2940(s), 2860 (m), 1588 (w), 1482 (w), 1468 (m), 1460 (m), 1440 (s), 1380(m), 1360 (w), 1310 (w), 1253 (m), 1230 (m), 1210 (m), 1110 (s), 1080(m), 1050 (m), 1018 (m), 1000 (m), 995 (m), 860 (m), 832 (s), 800 (m),708 (m), 680 (m), 652 (m) cm⁻¹; ¹H NMR (500 MHZ, CDCl₃; concentrationdependent) d 7.81-7.67 (m, 15 H), 4.92 (d, J=9.7 Hz, 1 H), 3.50(apparent t, J=5.3 Hz, 1 H), 3.38 (ddd, J=14.9, 14.9, 1.5 Hz, 1 H), 3.25(ddd, J=15.6, 11.1, 11.1 Hz, 1 H), 2.42 (ddq, J=9.7, 6.6, 6.6 Hz, 1 H),2.10-2.00 (m, 1 H), 1.53 (s, 3 H), 1.43 (s, 3 H), 0.83 (s, 9 H), 0.81(d, J=6.7 Hz, 3 H), 0.75 (d, J=6.8 Hz, 3 H), 0.03 (s, 3 H), −0.02 (s, 3H); ¹³C NMR (125 MHZ, CDCl₃) d, 135.3 (J_(cp)=2.8 Hz), 133.3 (J_(cp)=9.9Hz), 131.0, 130.6 (J_(cp)=12.4 Hz), 128.0, 118.2 (J_(cp)=85.6 Hz), 80.4(J_(cp)=13.3 Hz), 36.0, 33.0 (J_(cp)=4.0 Hz), 26.1, 25.6, 25.1(J_(cp)=50.8 Hz), 18.3, 18.1, 17.9, 16.4, −3.3, −4.0; high resolutionmass spectrum (FAB, NBA) m/z 531.3221 [(M−I)⁺; calcd for C₃₄H₄₈OPSi:531.3213].

Olefin (−)-47: Colorless oil; [α]²³ _(D) −14° © 0.36, CHCl₃); IR (CHCl₃)2960 (s), 2930 (s), 2860 (s), 1470 (m), 1460, 1370 (m), 1360 (m), 1250(m), 1206 (w), 1165 (m), 1140 (m), 1070 (s), 1020 (s), 1000 (m), 932(w), 908 (w), 897 (w), 853 (m), 830 (s) cm⁻¹; ¹H NMR (500 MHZ, CDCl₃) d3.63 (d, br, J=3.6 Hz, 1 H), 2.50 (apparent q, J=7.3 Hz, 1 H), 2.28(ddd, J=15.5, 7.7, 0.8 Hz, 1 H), 2.13-2.03 (m, 1 H), 1.99-1.91 (m, 1 H),1.60 (apparent br s, 3 H), 1.57 (apparent d, J=0.8 Hz, 1 H), 0.94 (d,J=6.7 Hz, 3 H), 0.91 (d, J=7.4 Hz, 3 H), 0.85 (s, 9 H), 0.01 (apparents, 6 H); ¹³C NMR (125 MHZ, CDCl₃) d 138.9 (q), 122.0 (q), 82.9, 46.1,36.4, 35.8 (CH₂), 25.9, 21.2, 20.4, 18.3 (q), 18.0, 14.3, −4.6, −4.8;high resolution mass spectrum (CI, NH₃) m/z 269.2310 [(M+H)⁺; calcd forC₁₆H₃₃OSi: 269.2300].

Olefin (−)-48: Colorless oil; [α]²³ _(D) −3.8° © 0.24, CHCl₃); IR(CHCl₃) 2953 (s), 2925 (s), 2880 (m), 2855 (m), 1638 (w), 1470 (m), 1460(m), 1385 (w), 1373 (m), 1360 (w), 1250 (m), 1135 (m), 1117 (m), 1100(m), 1075 (m), 1028 (m), 1000 (m), 932 (w), 865 (m), 830 (s) cm⁻¹; ¹HNMR (500 MHZ, C₆D₆) d 4.84-4.83 (m, 1 H), 4.79-4.77 (m, 1 H), 3.46(apparent t, J=5.3 Hz, 1 H), 1.94-1.88 (m, 1 H), 1.87-1.78 (m, 2 H),1.73 (ddd, J=12.4, 7.3, 7.3 Hz, 1 H), 1.66 (apparent dd, J=1.3, 0.8 Hz,3 H), 1.45 (ddd, J=12.2, 10.3, 8.7 Hz, 1 H), 1.00 (d, J=6.9 Hz, 3 H),0.99 (s, 9 H), 0.96 (d, J=6.7 Hz, 3 H), 0.06 (s, 3 H), 0.05 (s, 3 H);¹³C NMR (125 MHZ, C₆D₆) d 147.4 (q), 110.3 (CH₂), 82.3, 53.1, 45.4, 37.5(CH₂), 37.3, 26.1, 19.3, 18.4 (q), 18.0, 15.6, −4.4, −4.5; highresolution mass spectrum (CI, NH₃) m/z 269.2315 [(M+H)⁺; calcd forC₁₆H₃₃OSi: 269.2300].

EXAMPLE 40

Alcohol (+)-51.

A solution of olefin (+)-44 (70.9 mg, 0.28 mmol) in EtOH/EtOAc (1:8, 4.5mL) was treated with Pd/C (10% wet, E101 NE/W, 15.2 mg) under H₂atmosphere for 18 h. The mixture was then filtered through a shortsilica pipet and concentrated. Flash chromatography (5% ethylacetate/hexane) provided (+)-51 (70.8 mg, 100% yield) as a colorlessoil. [α]²³ _(D) +28° © 0.15, CHCl₃); IR (CHCl₃) 3680 (w), 3620 (w), 3500(w, br), 3010 (m), 2960 (s), 2935 (s), 2900 (m), 2885 (m), 2860 (m),1522 (w) 1510 (w), 1470 (m), 1426 (m), 1420 (m), 1412 (m), 1387 (m),1370 (m), 1255 (m), 1205 (m), 1070 (m), 1030 (m), 1013 (m), 1002 (m),980 (m), 925 (m), 833 (s), 720 (m), 665 (m), 658 (m) cm⁻¹; ¹H NMR (500MHZ, CDCl₃) d 3.60-3.56 (m, 2 H), 3.46 (dd, J=5.5, 3.8 Hz, 1 H), 2.46(br s, 1 H), 1.89-1.81 (m, 1 H), 1.74-1.66 (m, 1 H), 1.64-1.56 (m, 1 H),1.21 (ddd, J=13.3, 8.9, 4.6 Hz, 1 H), 1.09 (ddd, J=13.7, 9.6, 5.3 Hz, 1H), 0.94 (d, J=7.0 Hz, 3 H), 0.90 (s, 9 H), 0.88 (d, J=6.6 Hz, 3 H),0.86 (d, J=6.9 Hz, 3 H), 0.83 (d, J=6.6 Hz, 3 H), 0.095 (s, 3 H), 0.07(s, 3 H); ¹³CNMR (125 MHZ, CDCl₃) d 81.3, 66.3, 42.5, 37.8, 35.7, 26.1,25.4, 23.8, 21.8, 16.4, 15.1, −3.9, −4.1; high resolution mass spectrum(CI, NH₃) m/z 289.2565 [(M+H)⁺; calcd for C₁₆H₃₇O₂Si: 289.2562].

EXAMPLE 41

Iodide (+)-52.

A solution of alcohol (+)-51 (150 mg, 0.520 mmol), PPh₃ (205 mg, 0.780mmol) and imidazole (53 mg, 0.780 mmol) in benzene/ether (1:2; 6.0 mL)was treated with iodine (198 mg, 0.780 mmol) under vigorous stirring atroom temperature. After 40 min, the mixture was diluted with ether (100mL), washed with saturated Na₂S₂O₃ (50 mL), brine (100 mL), dried overMgSO₄, filtered and concentrated. Flash chromatography (hexane) provided(+)-51 (195 mg, 94% yield) as a colorless oil: [α]²³ _(D) +24.2° © 2.21,CHCl₃); IR (CHCl₃) 2960 (s), 2935 (s), 2900 (m), 2860 (s), 1470 (m),1463 (m), 1425 (w), 1405 (w), 1382 (m), 1368 (m), 1360 (m), 1290 (w),1255 (s), 1190 (m), 1170 (m), 1082 (s), 1065 (m), 1028 (m), 1003 (m),970 (w), 932 (w), 832 (s) cm⁻¹; ¹H NMR (500 MHZ, CDCl₃) d 3.41 (dd,J=9.6, 3.7 Hz, 1 H), 3.38 (dd, J=6.3, 2.6 Hz, 1 H), 3.10 (dd, J=9.6, 7.5Hz, 1 H), 1.72-1.56 (m, 3 H), 1.17 (ddd, J=13.4, 8.3, 5.4 Hz, 1 H), 1.09(ddd, J=13.3, 5.9, 2.1 Hz, 1 H), 0.99 (d, J=6.8 Hz, 3 H), 0.89 (s, 9 H),0.88 (d, J=6.6 Hz, 3 H), 0.84 (d, J=6.6 Hz, 3 H), 0.81 (d, J=6.8 Hz, 3H), 0.09 (s, 3 H), 0.06 (s, 3 H); ¹³C NMR (125 MHZ, CDCl₃) d 79.1, 43.7,39.8, 33.8, 26.2, 25.3, 23.5, 22.0, 18.7, 18.5, 15.9, 14.4, −3.65,−3.71; high resolution mass spectrum (CI, NH₃) m/z 399.1572 [(M+H)⁺;calcd for C₁₆H₃₆OISi: 399.1580].

EXAMPLE 42

Wittig Reagent (+)-53.

A mixture of Iodide (+)-52 (195 mg, 0.489 mmol) and benzene (100 mL) wastreated with I-Pr₂NEt (85 μL, 0.488 mmol) and PPh₃ (1.28 g, 4.88 mmol),then heated at 70° C. for 24 h. The mixture was extracted with hexane(3×20 mL). The residue was purified by flash chromatography (3%MeOH/CHCl₃) furnishing (+)-53 (303 mg, 94% yield) as a white foam; [α]²³_(D) +3.3° © 2.14, CHCl₃); IR (CHCl₃) 2950 (s), 2930 (s), 2855 (m), 1588(w), 1482 (w), 1463 (m), 1438 (s), 1385 (m), 1365 (w), 1253 (m), 1225(m), 1207 (m), 1110 (s), 1080 (m), 1032 (m), 1000 (m), 832 (s), 804 (m),708 (m), 680 (m), 653 (m) cm⁻¹; ¹H NMR (500 MHZ, CDCl₃) d 7.83-7.67 (m,15 H), 3.70 (ddd, J=15.6, 11.0, 11.0 Hz, 1 H), 3.52 (dd, J=7.6, 1.7 Hz,1 H), 3.45 (apparent t, J=15.4 Hz, 1 H), 2.08-1.97 (m, 1 H), 1.70-1.62(m, 1 H), 1.51 (9 lines, J=6.5 Hz, 1 H), 1.09-0.97 (m, 2 H), 0.850 (s, 9H), 0.79 (d, J=6.7 Hz, 3 H), 0.77 (d, J=7.9 Hz, 3 H), 0.74 (d, J=6.5 Hz,3 H), 0.68 (d, J=6.8 Hz, 3 H), 0.12 (s, 3 H), 0.11 (s, 3 H); ¹³C NMR(125 MHZ, CDCl₃) d 135.2 (J_(cp)=2.7 Hz), 133.6 (J_(cp)=9.9 Hz), 130.6(J_(cp)=12.4 Hz), 118.5 (J_(cp)=85.5 Hz), 80.1 (J_(cp)=12.9 Hz), 43.5,33.6, 32.6 (J_(cp)=3.7 Hz), 26.2, 25.3 (J_(cp)=51.1 Hz), 25.0, 23.4,21.7, 18.6, 18.5, 13.7, −2.7, −3.8; high resolution mass spectrum(FAB,NBA) m/z 533.3369 [(M−I)⁺; calcd for C₃₄H₅₀OPSi: 533.3357].

EXAMPLE 43

Olefin (−)-54.

Phosphonium salt (−)-49 was dried azeotropically with anhydrous benzeneand heated at 50° C. under vacuum for 3 h before use. A solution of(−)-49 (97.7 mg, 0.0917 mmol) in THF (700 μL) was cooled to −78° C. andtreated with NaHMDS (1.0 M in THF, 85.5 μL, 0.0855 mmol). The mixturewas stirred for 20 min at 0° C., recooled to −78° C. and aldehyde C(28.0 mg, 0.0570 mmol) in THF (300 μL) was added. After 10 min at −78°C. and 2 h at room temperature, the mixture was quenched with saturatedaqueous NH₄Cl (1.0 mL) and extracted with ether (30 mL). The ethersolution was washed with water, brine (30 mL each), dried over MgSO₄,filtered and concentrated. Flash chromatography (2% ethylacetate/hexane) provided (−)-56 (50.0 mg, 76% yield) as a colorless oil:[α]²³ _(D) −44.9° © 2.09, CHCl₃); IR (CHCl₃) 2960 (s), 2930 (s), 2855(s), 1615 (m), 1587 (w), 1517 (m), 1463 (s), 1380 (m), 1360 (m), 1320(m), 1300 (m), 1250 (s), 1170 (m), 1160 (m); 1120-1000 (s, br), 990 (m),965 (m), 935 (m), 900 (m), 835 (s), 807 (m), 670 (m) cm⁻¹; ¹H NMR (500MHZ, CDCl₃) d 7.35 (d, J=8.7 Hz, 2 H), 6.85 (d, J=8.8 Hz, 2 H), 5.37 (s,1H), 5.27 (dd, J=11.2, 7.8 Hz, 1 H), 5.19 (apparent t, J=10.9 Hz, 1 H),5.08 (d, J=10.1 Hz, 1 H), 5.06 (d, J=2.2 Hz, 1 H), 4.68 (apparent t,J=9.1 Hz, 1 H), 4.08 (dd, J=11.2, 4.7 Hz, 1 H), 3.78 (s, 3 H), 3.68(apparent t, J=10.1 Hz, 1 H), 3.61 (dd, J=7.1, 1.7 Hz, 1 H), 3.53(apparent t, J=2.6 Hz, 1 H), 3.50 (dd, J=9.9, 1.6 Hz, 1 H), 3.46(apparent t, J=11.1 Hz, 1 H), 3.25 (apparent t, J=5.3 Hz, 1 H),2.71-2.58 (m, 1 H), 2.68 (dq, J=12.8, 7.4 Hz, 1 H), 2.62 (dq, J=12.8,7.4 Hz, 1 H), 2.50 (m, 1 H), 2.30 (apparent t, J=12.2 Hz, 1 H),2.08-2.01 (m, 1 H), 1.98-1.90 (m, 1 H), 1.88 (dqd, J=7.1, 7.1, 1.7 Hz, 1H), 1.82 (apparent qt, J=7.1, 2.6 Hz, 1 H), 1.65 (br d, J=12.4 Hz, 1 H),1.62-1.57 (m, 2 H), 1.56 (d, J=0.4 Hz, 3 H), 1.38 (ddd, J=13.6, 10.7,1.5 Hz, 1 H), 1.29-1.22 (apparent t, J=7.4 Hz, 3 H), 1.00 (d, J=7.1 Hz,3 H), 0.94 (d, J=7.3 Hz, 3 H), 0.930 (d, J=6.9 Hz, 3 H), 0.925 (d, J=7.1Hz, 3 H), 0.90 (s, 18 H), 0.89 (s, 9 H), 0.86 (s, 9 H), 0.74 (apparentd, J=6.6 Hz, 6 H), 0.73 (d, J=6.1 Hz, 3 H), 0.05 (s, 3 H), 0.04 (s, 3H), 0.03 (s, 3 H), 0.019 (s, 3 H), 0.017 (s, 3 H), 0.013 (s, 3 H), 0.009(s, 3 H), 0.00 (s, 3 H); ¹³C NMR (125 MHZ, CDCl₃) d 159.8, 134.4, 131.9,131.8, 131.5, 131.4, 127.3, 113.4, 101.0, 83.4, 80.9, 80.4, 78.5, 76.7,76.5, 74.2, 73.3, 65.5, 55.2, 42.5, 41.9, 38.2, 37.5, 37.1, 35.4, 34.4,33.8, 26.3, 26.2, 26.0, 25.9, 25.1, 23.2, 18.5, 18.4, 18.12, 18.08,17.0, 16.6, 15.6, 14.4, 12.7, 12.1, 11.6, 10.9, −2.7, −3.5, −3.66,−3.69, −4.2, −4.5, −4.9, −5.0; high resolution mass spectrum (FAB, NBA)m/z 1171.7799 [(M+Na)⁺; calcd for C₆₃H₁₂₀O₈SSi₄Na: 1171.7781].

EXAMPLE 44

Hydroxy Diene (−)-55.

A solution of the olefin (−)-54 (49.8 mg, 0.0434 mmol) in CH₂Cl₂ (4.4mL) was cooled to −78° C. and DIBAL (1.0 M in toluene, 430 μL, 0.430mmol) was added over 5 min. After 10 min at −78° C. and 30 min at 0° C.,the reaction was quenched with saturated aqueous Rochelle's salt (500μL). The mixture was diluted with ether (60 mL), washed with saturatedaqueous Rochelle salt, brine (30 mL each), dried over MgSO₄, filteredand concentrated. Flash chromatography (5% ethyl acetate/hexane)furnished (−)-57 (38.0 mg, 88% yield) as a colorless oil: [α]²³ _(D)−32° © 1.90, CHCl₃); IR (CHCl₃) 3500 (w, br), 2960 (s), 2935 (s), 2900(m), 2885 (m), 2860 (s), 1610 (m), 1585 (w), 1510 (m), 1470 (m), 1460(m), 1400 (m), 1375 (m), 1360 (m), 1300 (m), 1250 (s), 1170 (m), 1095(m), 1080 (m), 1047 (s), 1000 (m), 960 (m), 950 (m), 933 (m), 835 (s),805 (m), 665 (m) cm⁻¹; ¹H NMR (500 MHZ, CDCl₃) d 7.24 (d, J=8.6 Hz, 2H), 6.85 (d, J=8.6 Hz, 2 H), 5.27 (dd, J=11.4, 7.8 Hz, 1 H), 5.20(apparent t, J=10.3 Hz, 1 H), 5.10 (d, J=10.0 Hz, 1 H), 5.05 (d, J=2.2Hz, 1 H), 4.68 (apparent t, J=9.2 Hz, 1 H), 4.49 (ABq, J_(AB)=10.4 Hz,Δδ_(AB)=23.4 Hz, 2 H), 3.78 (s, 3 H), 3.73 (ddd, J=10.7, 4.0, 4.0 Hz, 1H), 3.68 (apparent t, J=10.4 Hz, 1 H), 3.57 (ddd, J=10.6, 5.1, 5.1 Hz, 1H), 3.53 (dd, J=5.4, 3.4 Hz, 1 H), 3.50 (apparent t, J=5.2 Hz, 1 H),3.35 (apparent t, J=5.5 Hz, 1 H), 3.26 (apparent t, J=5.2 Hz, 1 H), 2.68(dq, J=12.8, 7.4 Hz, 1 H), 2.61 (dq, J=12.8, 7.5 Hz, 1 H), 2.71-2.58 (m,2 H), 2.51-2.44 (m, 1 H), 2.22 (apparent t, J=12.4 Hz, 1 H), 1.99-1.86(m, 3 H), 1.81 (apparent qt, J=7.1, 2.6 Hz, 1 H), 1.72 (br d, J=12.7 Hz,1 H), 1.62-1.57 (m, 1 H), 1.61 (s, 3 H), 1.56-1.48 (m, 1 H), 1.38 (ddd,J=13.5, 12.3, 1.4 Hz, 1 H), 1.27 (apparent t, J=7.4 Hz, 3 H), 1.03 (d,J=6.9 Hz, 3 H), 1.02 (d, J=6.8 Hz, 3 H), 0.95-0.92 (m, 9 H), 0.93 (s, 9H), 0.90 (s, 9 H), 0.89 (s, 9 H), 0.86 (s, 9 H), 0.74 (d, J=8.0 Hz, 3H), 0.73 (d, J=7.0 Hz, 3 H), 0.08 (s, 6 H), 0.05 (s, 3 H), 0.024 (s, 3H), 0.020 (s, 3 H), 0.012 (s, 3 H), 0.009 (s, 3 H), 0.006 (s, 3 H); ¹³CNMR (125 MHZ, CDCl₃) d 159.4, 134.4, 132.3, 131.7, 130.9, 130.4, 129.3,114.0, 86.3, 80.9, 80.4, 77.6, 76.5, 75.3, 74.2, 65.6, 65.5, 55.3, 42.6,41.9, 40.0, 37.6, 37.0, 36.8, 35.9, 35.2, 34.5, 26.30, 26.27, 25.9,25.8, 25.1, 23.2, 18.53, 18.47, 18.13, 18.07, 17.1, 16.6, 15.7, 15.6,14.4, 13.6, 11.6, 11.4, −2.8, −3.2, −3.4, −3.6, −4.2, −4.5, −4.9; highresolution mass spectrum (FAB, NBA) m/z 1173.7859 [(M+Na)⁺; calcd forC₆₃H₁₂₂O₈SSi₄Na: 1173.7835].

EXAMPLE 45

Aldehyde (−)-56.

A solution of alcohol (−)-55 (13.8 mg, 0.0120 mmol) and Et₃N (42 μL,0.30 mmol) in CH₂Cl₂ (200 μL) was cooled to 0° C. and treated withSO₃.pyridine (40 mg, 0.251 mmol) in DMSO (600 μL). After 45 min at 0°C., the mixture was diluted with ethyl acetate (30 mL), washed withaqueous NaHSO₄ (1.0 M, 30 mL), brine (2×30 mL), dried over MgSO₄,filtered and concentrated. Pipette flash chromatography (3% ethylacetate/hexane) afforded (−)-56 (13.2 mg, 96% yield) as a colorless oil:[α]²³ _(D) −32.1° © 1.40, CHCl₃); IR (CHCl₃) 2960 (s), 2935 (s), 2880(m), 1720 (m), 1610 (m), 1512 (m), 1470 (m), 1460 (m), 1387 (m), 1380(m), 1360 (m), 1340 (m), 1320 (m), 1300 (m), 1250 (s), 1110 (s), 1098(s), 1080 (s), 1048 (s), 1002 (m), 988 (m), 965 (m), 950 (m), 935 (m),835 (s) cm⁻¹; ¹H NMR (500 MHZ, CDCl₃) d 9.78 (d, J=2.5 Hz, 1 H), 7.20(d, J=8.6 Hz, 2 H), 6.85 (d, J=8.7 Hz, 2 H), 5.27 (dd, J=11.1, 7.8 Hz, 1H), 5.19 (apparent t, J=10.4 Hz, 1 H), 5.10 (d, J=10.0 Hz, 1 H), 5.05(d, J=2.1 Hz, 1 H), 4.67 (apparent t, J=8.9 Hz, 1 H), 4.45 (apparent s,2 H), 3.78 (s, 3 H), 3.68 (apparent t, J=10.2 Hz, 1 H), 3.58-3.56 (m, 2H), 3.51 (apparent t, J=2.6 Hz, 1 H), 3.25 (apparent t, J=5.2 Hz, 1 H),2.73 (dqd, J=7.1, 6.0, 2.6 Hz, 1 H), 2.70-2.57 (m, 3 H), 2.51-2.44 (m, 1H), 2.23 (apparent t, J=12.4 Hz, 1 H), 1.98-1.85 (m, 2 H), 1.81(apparent qt, J=7.1, 2.6 Hz, 1 H), 1.67 (br d, J=13.0 Hz, 1 H), 1.60 (s,3 H), 1.62-1.50 (m, 2H), 1.37 (ddd, J=13.8, 10.4, 1.5 Hz, 1 H), 1.26(apparent t, J=7.4 Hz, 3 H), 1.10 (d, J=7.0 Hz, 3 H), 1.02 (d, J=7.0 Hz,3 H), 0.938 (d, J=7.1 Hz, 3 H), 0.932 (d, J=7.8 Hz, 3 H), 0.919 (s, 9H), 0.918 (d, J=6.6 Hz, 3 H), 0.90 (s, 9 H), 0.88 (s, 9 H), 0.86 (s, 9H), 0.732 (d, J=6.7 Hz, 3 H), 0.726 (d, J=6.8 Hz, 3 H), 0.07 (s, 3 H),0.053 (s, 3 H), 0.047 (s, 3 H), 0.02 (s, 6 H), 0.009 (s, 3 H), 0.005 (s,6 H); ¹³C NMR (125 MHZ, CDCl₃) d 204.6, 159.3, 134.4, 132.3, 131.8,130.8, 130.3, 129.1, 128.3, 113.8, 82.6, 80.9, 80.4, 76.5, 74.5, 74.2,65.5, 55.3, 49.5, 42.5, 41.9, 40.3, 37.1, 36.8, 35.4, 34.9, 34.4, 26.3,26.2, 25.9, 25.8, 25.1, 23.2, 18.49, 18.45, 18.12, 18.07, 17.0, 16.6,15.6, 14.4, 13.3, 12.1, 11.6, 11.4, −2.8, −3.3, −3.4, −3.7, −4.2, −4.5,−4.9, −5.0; high resolution mass spectrum (FAB, NBA) m/z 1171.7670[(M+Na)⁺; calcd for C₆₃H₁₂₀O₈SSiNa: 1171.7676].

EXAMPLE 46

Tetraene (−)-57.

A solution of Ph₂PCH₂CH═CH₂ (40 μL, 0.19 mmol) in THF (1.0 mL) wascooled to −78° C. and t-BuLi (1.7 M in pentane, 72.0 μL, 0.122 mmol) wasadded. The mixture was stirred at 0° C. for 30 min, recooled to −78° C.and treated with Ti(OiPr)₄ (45 μL, 0.15 mmol). After 30 min, a cold(−78° C.) solution of the aldehyde (−)-56 (30.2 mg, 0.0262 mmol) in THF(1.0 mL) was introduced via cannula, and the resultant mixture wasstirred for 10 min at −78° C. and 1 h at 0° C. MeI (20 μL, 0.32 mmol)was then added, and the reaction was maintained at 0° C. for 30 min,warmed to room temperature, protected from light with aluminum foil, andstirred overnight. The reaction mixture was diluted with ether (30 mL),washed with aqueous NaHSO₄ (1.0 M), brine (30 mL each), dried overMgSO₄, filtered and concentrated. Flash chromatography (2% ethylacetate/hexane) gave a 16:1 mixture of Z/E isomers (20.0 mg, 70% yield)as an oil. Pipette flash chromatography. (20% benzene/hexane) furnishedthe Z-olefin (−)-57 as a colorless oil: [α]²³ _(D) −57.2° © 2.56,CHCl₃); IR (CHCl₃) 3015 (m), 2960 (s), 2940 (s), 2900 (m), 2885 (m),2860 (s), 1613 (w), 1515 (m), 1475 (m), 1465 (m), 1390 (w), 1380 (w),1360 (w), 1250 (s), 1110 (m), 1100 (m), 1080 (m), 1050 (s), 1003 (m),,963 (w), 950 (w), 835 (s), 800 (m), 790 (m), 770 (m), 700 (w), 690 (w),670 (w), 655 (w) cm⁻¹; ¹H NMR (500 MHZ, CDCl₃) d 7.25 (d, J=8.2 Hz, 2H), 6.84 (d, J=8.7 Hz, 2 H), 6.57 (dddd, J=16.8, 11.0, 11.0, 0.7 Hz, 1H), 6.00 (apparent t, J=11.1 Hz, 1 H), 5.55 (apparent t, J=10.5 Hz, 1H), 5.26 (dd, J=11.2, 7.8 Hz, 1 H), 5.20-5.16 (m, 2 H), 5.09 (d, J=10.1Hz, 1 H), 5.05 (d, J=2.2 Hz, 1 H), 5.03 (d, J=10.0 Hz, 1 H), 4.67(apparent t, J=9.1 Hz, 1 H), 4.49 (ABq, J_(AB)=10.6 Hz, Δδ_(AB)=41.3 Hz,2 H), 3.78 (s, 3 H), 3.68 (apparent t, J=10.2 Hz, 1 H), 3.52 (apparentt, J=2.6 Hz, 1 H), 3.43 (dd, J=4.8, 3.9 Hz, 1 H), 3.24-3.21 (m, 2 H),3.01-2.94 (m, 1 H), 2.67 (dq, J=12.8, 7.4 Hz, 1 H), 2.61 (dq, J=12.8,7.5 Hz, 1 H), 2.71-2.57 (m, 1 H), 2.46-2.39 (m, 1 H), 2.00 (apparent t,J=12.4 Hz, 1 H), 1.83-1.73 (m, 3 H), 1.64 (br d, J=14.0 Hz, 1 H),1.62-1.52 (m, 2 H), 1.55 (d, J=0.5 Hz, 3 H), 1.36 (ddd, J=13.7, 10.8,1.5 Hz, 1 H), 1.26 (d, J=7.4 Hz, 3 H), 1.25 (d, J=7.4 Hz, 3 H), 1.08 (d,J=6.8 Hz, 3 H), 0.98 (d, J=6.8 Hz, 3 H), 0.94 (d, J=7.1 Hz, 3 H), 0.93(s, 9 H), 0.90 (s, 9 H), 0.89 (s, 9 H), 0.89-0.86 (m, 3 H), 0.86 (s, 9H), 0.73 (d, J=6.8 Hz, 3 H), 0.70 (d, J=6.7 Hz, 3 H), 0.08 (s, 6 H),0.05 (s, 3 H), 0.02 (s, 3 H), 0.013 (s, 3 H), 0.010 (s, 6 H), −0.02 (s,3 H); ¹³C NMR (125 MHZ, CDCl₃) d 159.1, 134.5, 134.3, 132.2, 131.9,131.8, 131.2, 129.13, 129.07, 117.6, 113.7, 84.6, 80.9, 80.5, 76.5,75.0, 74.2, 65.5, 55.3, 42.5, 41.9, 40.2, 37.2, 36.1, 35.4, 35.3, 34.5,29.7, 26.3, 26.0, 25.9, 25.1, 23.1, 18.7, 18.6, 18.5, 18.14, 18.09,17.0, 16.8, 15.6, 14.8, 14.4, 11.6, 10.6, −2.8, −3.2, −3.3, −3.6, −4.2,−4.5, −4.90, −4.93; high resolution mass spectrum (FAB, NBA) m/z1195.8001 [(M+Na)⁺; calcd for C₆₆H₁₂₄O₇SSi₄Na: 1195.8042].

EXAMPLE 47

Lactone (−)-58.

A solution of diene (−)-57 (7.0 mg, 0.00597 mmol) in THF/CH₃CN (2:1,1.50 mL) was treated with pH 7.0 phosphate buffer (500 μL) and HgCl₂(215 mg). The suspension was stirred at room temperature for 40 min,diluted with ether (30 mL), washed with brine (2×30 mL), dried overMgSO₄, filtered and concentrated. Pipette flash chromatography (5% ethylacetate/hexane) provided a mixture of lactols as a colorless oil whichwas further treated with DMSO (1.0 mL) and Ac₂O (200 mL) at roomtemperature for 2 days. The mixture was diluted with ether (30 mL),washed with saturated NaHCO₃ (30 mL), brine (30 mL), dried over MgSO₄,filtered and concentrated. Pipette flash chromatography (2% ethylacetate/hexane) provided (−)-58 (5.5 mg, 82% yield from (−)-57) as acolorless oil: [α]²³ _(D) −31.6 © 0.23, CHCl₃); IR (CHCl₃) 3015 (m),2960 (s), 2930 (s), 2880 (m), 2855 (m), 1725 (m), 1610 (w), 1510 (w),1460 (m), 1385 (m), 1373 (m), 1360 (m), 1300 (w), 1250 (s), 1230 (m),1200 (m), 1170 (m), 1120 (m), 1097 (m), 1060 (m), 1045 (s), 1020 (m),1003 (m), 980 (w), 955 (w), 930 (w), 905 (w), 867 (m), 835 (s), 800 (m),695 (m), 670 (m), 660 (m) cm⁻¹; ¹H NMR (500 MHZ, CDCl₃) d 7.25 (d, J=9.0Hz, 2 H), 6.84 (d, J=8.7 Hz, 2 H), 6.57 (ddd, J=16.7, 10.6, 10.6 Hz, 1H), 6.00 (apparent t, J=11.0 Hz, 1 H), 5.55 (apparent t, J=10.5 Hz, 1H), 5.26 (dd, J=11.1, 7.9 Hz, 1 H), 5.19 (dd, J=15.4, 1.4 Hz, 1 H), 5.18(apparent t J=10.1 Hz, 1 H), 5.10 (d, J=10.2 Hz, 1 H), 5.01 (d, J=10.0Hz, 1 H), 4.75 (apparent t, J=9.2 Hz, 1 H), 4.50 (ddd, J=10.5, 1.3, 1.3Hz, 1 H), 4.50 (ABq, J_(AB)=10.6 Hz, Δδ_(AB)=42.6 Hz, 2 H), 3.78 (s, 3H), 3.60 (apparent t, J=2.4 Hz, 1 H), 3.42 (dd, J=5.1, 3.7 Hz, 1 H),3.23 (dd, J=7.5, 3.7 Hz, 1 H), 3.20 (apparent t, J=5.4 Hz, 1 H),3.01-2.94 (m, 1 H), 2.60 (qd, J=7.7, 2.6 Hz, 1 H), 2.62-2.55 (m, 1 H),2.45-2.38 (m, 1 H), 1.98 (apparent t, J=12.3 Hz, 1 H), 1.84-1.67 (m, 3H), 1.63 (br d, J=13.2 Hz, 1H), 1.52 (s, 3 H), 1.55-1.48 (m, 1 H), 1.20(d, J=7.6 Hz, 3 H), 1.09 (d, J=6.8 Hz, 3 H), 0.98 (d, J=6.8 Hz, 3 H),0.93 (apparent d, J=6.7 Hz, 6 H), 0.93 (s, 9 H), 0.89 (s, 9 H), 0.86 (s,9 H), 0.85 (s, 9 H), 0.84 (d, J=6.8 Hz, 3 H), 0.69 (d, J=6.7 Hz, 3 H),0.085 (s, 3 H), 0.079 (s, 3 H), 0.051 (s, 3 H), 0.046 (s, 3 H), 0.042(s, 3 H), 0.029 (s, 3 H), 0.028 (s, 3 H), −0.02 (s, 3 H); ¹³C NMR (125MHZ, CDCl₃) d 173.2, 159.1, 134.4, 133.4, 132.4, 132.2, 131.9., 131.3,131.2, 129.11, 129.09, 117.6, 113.7, 84.6, 80.5, 76.9, 75.0, 74.9, 64.6,55.3, 44.1, 42.7, 40.1, 37.5, 36.0, 35.44, 35.37, 35.2, 34.2, 26.31,26.28, 25.9, 25.7, 23.0, 18.7, 18.6, 18.4, 18.1, 18.0, 17.1, 16.5, 16.4,14.9, 14.1, 10.5, −3.0, −3.2, −3.3, −4.3, −4.4, −4.5, −4.8, −4.9; highresolution mass spectrum (FAB, NBA) m/z 1149.7836 [(M+Na)⁺; Calcd forC₆₄H₁₁₈O₈Si₄Na: 1149.7802].

EXAMPLE 48

Alcohol (−)-59.

A solution of (−)-58 (4.0 mg, 0.00355 mmol) in CH₂Cl₂ (500 μL) wastreated with H₂O (50 μL) and DDQ (3.0 mg, 0.0132 mmol) at 0° C. After 1h, the mixture was diluted with ethyl acetate (30 mL), washed with brine(3×30 mL), dried over MgSO₄, filtered and concentrated. Pipette flashchromatography (2% ethyl acetate/hexane) provided (−)-59 (3.4 mg, 95%yield) as a colorless oil: [α]²³ _(D) −20° © 0.34, CHCl₃); IR (film,CHCl₃ on NaCl plate) 3500 (w, br), 2960 (s), 2930 (s), 2890 (s), 2855(s), 1740 (m), 1460 (m), 1405 (m), 1380 (m), 1360 (s), 1253 (m), 1220(m), 1120 (s), 1093 (s), 1075 (s), 1045 (s), 1022 (s), 1002 (m), 980(m), 933 (m), 902 (m), 833 (s), 808 (m), 770 (s), 663 (m) cm⁻¹; ¹H NMR(500 MHZ, CDCl₃) d 6.61 (ddd, J=16.8, 10.9, 10.9 Hz, 1 H), 6.13(apparent t, J=11.0 Hz, 1 H), 5.32 (apparent t, J=10.5 Hz, 1 H), 5.28(dd, J=11.1, 7.9 Hz, 1 H), 5.24-5.21 (m, 1 H), 5.19 (apparent t, J=10.3Hz, 1 H), 5.14 (d, J=10.2 Hz, 1 H), 5.06 (d, J=10.0 Hz, 1 H), 4.76(apparent t, J=9.3 Hz, 1 H), 4.50 (apparent t, J=9.9 Hz, 1 H), 3.62(apparent t, J=2.4 Hz, 1 H), 3.60 (dd, J=5.5, 3.4 Hz, 1 H), 3.32 (br d,J=5.3 Hz, 1 H), 3.24 (apparent t, J=5.1 Hz, 1 H), 2.79 (ddq, J=9.9, 6.7,6.7 Hz, 1 H), 2.60 (qd, J=7.6, 2.7 Hz, 1 H), 2.63-2.57 (m, 1 H),2.50-2.45 (m, 1 H), 2.16 (apparent t, J=12.3 Hz, 1 H), 1.90-1.77 (m, 3H), 1.75-1.69 (m, 2 H), 1.57 (s, 3 H), 1.60-1.50 (m, 1 H), 1.20 (d,J=7.6 Hz, 3 H), 0.96 (d, J=6.8 Hz, 3 H), 0.95 (d, J=6.6 Hz, 3 H),0.95-0.93 (m, 6 H), 0.91 (s, 9 H), 0.89 (s, 9 H), 0.89-0.84 (m, 3 H),0.87 (s, 9 H), 0.85 (s, 9 H), 0.73 (d, J=6.8 Hz, 3 H), 0.07 (apparent s,6 H), 0.052 (s, 3 H), 0.051 (s, 3 H), 0.04 (apparent s, 6 H), 0.03 (s, 3H), −0.01 (s, 3 H); ¹³C NMR (125 MHZ, CDCl₃) d 173.3, 134.7, 133.5,132.5, 132.1, 132.0, 131.5, 131.0, 118.4, 80.5, 78.8, 76.4, 74.9, 64.7,44.1, 42.7, 38.0, 37.4, 36.3, 36.1, 35.2, 35.1, 34.2, 26.3, 26.2, 25.9,25.7, 23.2, 18.5, 18.1, 18.0, 17.3, 17.2, 16.4, 16.1, 14.1, 13.7, 9.4,−3.0, −3.3, −3.6, −4.34, −4.36, −4.5, −4.8; high resolution massspectrum (FAB, NBA) m/z 1029.7273 [(M+Na)⁺; calcd for C₅₆H₁₁₀O₇Si₄Na:1029.7226].

EXAMPLE 49

Carbamate (−)-60.

A solution of alcohol (−)-59 (2.2 mg, 0.00219 mmol) in CH₂Cl₂ (500 μL)was treated with Cl₃CON═C═O (20 μL, 0.168 mmol) at room temperature.After 30 min, the mixture was diluted with regular CH₂Cl₂ (2.0 mL) andtreated with neutral Al₂O₃ (500 mg). The mixture was stirred at roomtemperature for 2 h, filtered through a short silica plug, andconcentrated. Pipette flash chromatography (10% ethyl acetate/hexane)provided (−)-60 (1.9 mg, 83% yield) as a colorless oil: [α]²³ _(D) −37°© 0.19, CHCl₃); IR (film, CHCl₃ on NaCl plate) 3510 (m), 3360 (m, br),3180 (m), 2960 (s), 2930 (s), 2880 (s), 2855 (s), 1730 (s, br), 1596(m), 1460 (s), 1385 (s), 1362 (s), 1325 (m), 1255 (s), 1220 (m), 1100(s), 1043 (s), 983 (m), 937 (m), 904 (m), 832 (s), 770 (s), 663 (m)cm⁻¹; ¹H NMR (500 MHZ, CDCl₃) d 6.58 (dddd, J=16.8, 10.6, 10.6, 0.7 Hz,1 H), 6.01 (apparent t, J=11.0 Hz, 1 H), 5.36 (apparent t, J=10.4 Hz, 1H), 5.27 (dd, J=11.1, 7.9 Hz, 1 H), 5.22-5.16 (m, 2 H), 5.12 (d, J=10.1Hz, 1 H), 5.03 (d, J=10.0 Hz, 1 H), 4.76 (apparent t, J=9.2 Hz, 1 H),4.71 (apparent t, J=6.1 Hz, 1 H), 4.50 (ddd, J=10.5, 10.5, 1.3 Hz, 1 H),4.44 (br s, 2 H), 3.62 (apparent t, J=2.4 Hz, 1 H), 3.42 (apparent t,J=4.5 Hz, 1 H), 3.22 (apparent t, J=5.3 Hz, 1 H), 2.98 (ddq, J=10.1,6.6, 6.6 Hz, 1 H), 2.60 (qd, J=7.6, 2.7 Hz, 1 H), 2.63-2.55 (m, 1 H),2.48-2.41 (m, 1 H), 2.09 (apparent t, J=12.4 Hz, 1 H), 1.93-1.88 (m, 1H), 1.87-1.77 (m, 2 H), 1.71 (ddd, J=14.1, 10.8, 1.6 Hz, 1 H), 1.67 (brd, J=13.7 Hz, 1 H), 1.56 (apparent s, 3 H), 1.55-1.50 (m, 1 H), 1.21 (d,J=7.6 Hz, 3 H), 0.98 (d, J=6.8 Hz, 3 H), 0.95 (d, J=7.0 Hz, 3 H), 0.94(d, J=7.5 Hz, 3 H), 0.918 (d, J=6.8 Hz, 3 H), 0.915 (s, 9 H), 0.89 (s, 9H), 0.86 (s, 9 H), 0.853 (d, J=6.4 Hz, 3 H), 0.847 (s, 9 H), 0.70 (d,J=6.8 Hz, 3 H), 0.09 (s, 3 H), 0.07 (s, 3 H), 0.053 (s, 3 H), 0.051 (s,3 H), 0.040 (s, 3 H), 0.037 (s, 3 H), 0.03 (s, 3 H), −0.02 (s, 3 H); ¹³CNMR (125 MHZ, CDCl₃) d 173.3, 156.9, 133.6, 133.5, 132.4, 132.1, 131.9,131.4, 129.8, 118.0, 80.5, 78.9, 74.9, 64.6, 44.2, 42.7, 37.8, 37.4,36.0, 35.3, 35.2, 34.5, 34.2, 26.3, 26.2, 25.9, 25.7, 23.0, 18.5, 18.4,18.1, 18.0, 17.5, 17.1, 16.44, 16.38, 14.1, 13.7, 10.1, −3.0, −3.4,−3.6, −4.4, −4.5, −4.8; high resolution mass spectrum (FAB, NBA) m/z1072.7264 [(M+Na)⁺; calcd for C₅₇H₁₁₁NO₈Si₄Na: 1072.7283].

EXAMPLE 50

Discodermolide [(−)-1].

A solution of olefin (−)-60 (5.8 mg, 5.5 mmol) in 48% HF—CH₃CN (1:9, 1.0mL) was stirred at room temperature for 12 h, then quenched withsaturated aqueous NaHCO₃ (5.0 mL). The mixture was extracted with ethylacetate (3×10 mL). The combined organic extracts were washed with brine(5.0 mL), dried over MgSO₄, filtered and concentrated. Pipette flashchromatography (gradient elution, 1:30 to 1:6 MeOH/CHCl₃) provided (−)-1(2.0 mg, 60% yield) as a white amorphous solid: [α]²³ _(D) −16° © 0.03,MeOH); IR (CHCl₃) 3690 (w), 3620 (w), 3540 (w), 3430 (w), 3020 (s), 2975(m), 2935 (m), 1740 (m), 1590 (w), 1540 (w), 1520 (w), 1467 (w), 1430(w), 1385 (m), 1330 (w), 1233 (s), 1210 (s), 1100 (w), 1045 (m), 1033(m), 975 (w), 930 (m), 910 (w), 793 (m), 777 (m), 765 (m), 750 (m), 705(m), 687 (m), 670 (m), 660 (m), 625 (w) cm⁻¹; ¹H NMR (500 MHZ, CDCl₃) d6.60 (dddd, J=16.8, 8.4, 8.4, 0.8 Hz, 1 H), 6.02 (apparent t, J=11.1 Hz,1 H), 5.51 (dd, J=11.2, 7.9 Hz, 1 H), 5.42 (ddd, J=10.6, 10.6, 0.6 Hz, 1H), 5.34 (apparent t, J=10.4 Hz, 1 H), 5.20 (dd, J=16.9, 1.9 Hz, 1 H),5.16 (d, J=10.0 Hz, 1 H), 5.11 (d, J=10.1 Hz, 1 H), 4.77-4.69 (m, 1 H),4.70 (dd, J=7.3, 4.2 Hz, 1 H), 4.60 (ddd, J=10.0, 10.0, 2.4 Hz, 1 H),4.56 (br s, 2 H), 3.73 (m, 1 H), 3.28 (m, 1 H), 3.18 (dd, J=6.8, 4.8 Hz,1 H), 2.98 (ddq, J=10.1, 6.9, 6.9 Hz, 1 H), 2.78 (ddq, J=9.8, 6.8, 6.8Hz, 1 H), 2.66 (qd, J=7.3, 4.6 Hz, 1 H), 2.60-2.55 (m, 1 H), 2.10-1.80(m, 10 H), 1.69 (ddd, J=14.4, 10.3, 3.1 Hz, 1 H), 1.64 (d, J=1.3 Hz, 3H), 1.30 (d, J=7.4 Hz, 3 H), 1.06 (d, J=6.9 Hz, 3 H), 1.00 (d, J=6.8 Hz,3 H), 0.99 (d, J=6.7 Hz, 3 H), 0.97 (d, J=6.8 Hz, 3 H), 0.94 (d, J=6.8Hz, 3 H), 0.82 (d, J=6.3 Hz, 3 H); ¹³C NMR (125 MHZ, CDCl₃) d 173.6,157.0, 134.4, 133.7, 133.4, 132.9, 132.2, 129.9, 129.8, 117.9, 79.1,78.9, 77.9, 75.7, 73.2, 64.4, 43.1, 41.0, 37.4, 36.1, 36.0, 35.8, 35.3,34.8, 33.1, 23.3, 18.4, 17.4, 15.6, 15.5, 13.7, 12.5, 9.0; highresolution mass spectrum (FAB, NBA) m/z 616.3840 [(M+Na)⁺; calcd forC₃₃H₅₅NO₈Na: 616.3826].

EXAMPLE 51 FIGS. 16 and 17

A. Tosylate 101

A solution of diene 16 (see, Smith, et al., J. Am. Chem. Soc. 1995, 117,12011) (1.15 g, 1.0 mmol) in anhydrous pyridine (10 mL) at 0° C. istreated with p-toluenesulfonyl chloride (286 mg, 1.5 mmol). The mixtureis allowed to warm to room temperature for 4-6 h. The pyridine isremoved in vacuo and the residue is purified by flash chromatography toafford tosylate 101.

B. Arene 102

Phenyllithium (2.7 mL, 1.8 M in cyclohexane-ether (70:30)) is addeddropwise to a solution of copper (I) iodide (460 mg, 2.4 mmol) inanhydrous diethyl ether (5 mL) at 0° C. To the resultant mixture isadded a solution of tosylate 101 (780 mg, 0.6 mmol) in ether (5 mL) andthe resultant mixture is warmed to room temperature with stirring. After4 h, saturated aqueous ammonium chloride (20 mL) is added. The layersare separated and the aqueous layer is extracted with ethyl acetate. Thecombined organics are dried over magnesium sulfate and concentrated invacuo. The residue is purified by flash chromatography to afford 102.

C. Lactol 103.

To a solution of 102 (120 mg, 0.1 mmol) in tetrahydrofuran-acetonitrile(15 mL, 2:1) is added phosphate buffer (pH 7, 5 mL) and mercury (II)chloride (272 mg, 1.0 mmol). The resultant mixture is stirred 1 h atroom temperature. The reaction mixture is diluted with ether (100 mL)and washed with saturated aqueous brine (2×50 mL), dried over magnesiumsulfate and concentrated in vacuo. The residue is purified by flashchromatography to afford 103 as a mixture of α and β anomers.

D. Lactone 104.

To a solution of 103 (84 mg, 0.070 mmol) in dimethyl sulfoxide (10 mL)is added acetic anhydride (2 mL). After 2 days at room temperature, themixture is diluted with ether (100 mL) and washed with saturated aqueoussodium bicarbonate (50 mL), saturated aqueous brine (50 mL), dried overmagnesium sulfate and concentrated in vacuo. The residue is purified byflash chromatography to afford 104.

E. Alcohol 105.

To a solution of 104 (56 mg, 0.050 mmol) in dichloromethane (3 mL) at 0°C. is added water (50 mL) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone(52 mg, 0.018 mmol). After 1 h, the reaction mixture is diluted withethyl acetate (50 mL), washed with saturated aqueous brine (3×25 mL),dried over magnesium sulfate and concentrated in vacuo. The residue ispurified by flash chromatography to afford 105.

F. Carbamate 106.

To a solution of 105 (10 mg, 0.010 mmol) in dichloromethane (2 mL) isadded trichloroacetyl isocyanate (0.12 mL, 1.00 mmol). After 30 min, thereaction mixture is diluted with dichloromethane (4 mL) and neutralalumina (1 g) is added. The resultant suspension is stirred anadditional 4 h. The reaction mixture is filtered and the concentratedfiltrate is chromatographed on silica gel to afford 106.

G. Tetrol 107.

A solution of 106 (10 mg, 0.0096 mmol) in 48% hydrofluoricacid-acetonitrile (1:9, 2 mL) is stirred at ambient temperature. After12 h, saturated aqueous sodium bicarbonate (25 mL) is added and themixture is extracted with ethyl acetate (3×20 mL). The combined organicsare dried over magnesium sulfate and concentrated in vacuo. The residueis purified by flash chromatography to afford 107.

EXAMPLE 52 FIGS. 18-20

A. Alcohol 203.

To a slurry of powdered 4-Å molecular sieves (2.0 g) in 100 mL ofanhydrous toluene is added boronate 202 (see, Roush, et al., J. Am.Chem. Soc. 1990, 112, 6348) (170 mL, 1.0 M in toluene). The resultantsolution is stirred 10 min at room temperature and then cooled to −78°C. A solution of aldehyde 201 (see, Solladie, et al., Tetrahedron Lett.1987, 28, 797) (113 mmol) in toluene (100 mL) is added over a 2 hperiod, after which the reaction is maintained at −78° C. for 10 h.Excess ethanolic sodium borohydride (ca. 0.75 g/10 mL) is added and thereaction mixture is warmed to 0° C. Aqueous 1 N sodium hydroxide (300mL) is added and the mixture is stirred vigorously for 2 h. The layersare separated and the aqueous layer is extracted with ether (5×300 mL).The combined organics are dried over potassium carbonate andconcentrated in vacuo. The residue is purified by flash chromatographyto afford 203.

B. Bis-silyl ether 204

A solution of 203 (75 mmol) in dimethylformamide (150 mL) is cooled to0° C. and treated with imidazole (150 mmol) and tert-butyldimethylsilylchloride (100 mmol). The resultant solution is warmed to roomtemperature. After 12 h, the reaction mixture is poured into 1500 mL ofwater and extracted with ether (3×200 mL). The ethereal extracts arewashed with water (2×50 mL) and saturated aqueous brine (50 mL), driedover magnesium sulfate and concentrated in vacuo. The residue ispurified by flash chromatography to afford 204.

C. Alcohol 205.

A solution of 204 (20 mmol) in 500 mL of methanol is cooled to −78° C.and treated with a stream of ozone and oxygen until the colorlesssolution is converted into a steel blue one. The crude reaction mixtureis cautiously quenched with sodium borohydride (100 mmol) and theresultant solution is warmed to room temperature. After 3 h, the excesssodium borohydride is destroyed by the cautious addition of water. Themethanol is removed in vacuo and the residue is partitioned betweensaturated aqueous ammonium chloride (200 mL) and ethyl acetate (200 mL).The layers are separated and the aqueous layer is further extracted withethyl acetate (2×100 mL) The combined organics are dried over anhydrousmagnesium sulfate and concentrated in vacuo. The residue is purified byflash chromatography to afford 205.

D. Triethylsilyl ether 206.

A solution of 205 (15 mmol) in dimethylformamide (30 mL) is cooled to 0°C. and treated with imidazole (30 mmol) and triethylsilyl chloride (20mmol). The resultant solution is warmed to room temperature. After 12 h,the reaction mixture is poured into 300 mL of water and extracted withether (3×40 mL). The ethereal extracts are washed with water (2×25 mL)and saturated aqueous brine (25 mL), dried over magnesium sulfate andconcentrated in vacuo. The residue is purified by flash chromatographyto afford 206.

E. Alcohol 207.

To a solution of 206 (6 mmol) in ethyl acetate-ethanol (8:1, 90 mL) isadded palladium on carbon (10% wet, 500 mg). The mixture is stirredunder hydrogen atmosphere for 3-6 h, then filtered and concentrated invacuo. The residue is purified by flash chromatography to afford 207.

F. Aldehyde 208.

To a −10° C. solution of 207 (13 mmol) and triethylamine (50 mmol) indichloromethane (26 mL) is added a solution of sulfur trioxide-pyridine(39 mmol) in dimethyl sulfoxide (50 mL). The mixture is stirred 1 h atroom temperature and diluted with ether (150 mL). The organic phase iswashed with aqueous sodium bisulfate (1 M, 100 mL), saturated aqueousbrine (4×100 mL), dried over magnesium sulfate, and concentrated invacuo. The residue is purified by flash chromatography to afford 208.

G. Wittig Product 209.

Phosphonium salt 15 (see, Smith, et al., J. Am. Chem. Soc. 1995, 117,12011) (0.2 mmol) is dissolved in anhydrous tetrahydrofuran (2 mL) andchilled to 0° C. A solution of sodium bis(trimethylsilyl)amide (0.2mmol, 1.0 M in tetrahydrofuran) is added and the reaction mixture isstirred 30 min at 0° C. After cooling to −78° C., a solution of aldehyde208 (0.1 mmol) in tetrahydrofuran (2 mL) is added and the mixture isstirred 10 min at −78° C. and 2 h at room temperature. Saturated aqueousammonium chloride (2 mL) is added and the resultant mixture is extractedwith ether (3×20 mL). The ethereal layer is washed with water (2×25 mL)and saturated aqueous brine (25 mL), dried over magnesium sulfate andconcentrated in vacuo. The residue is purified by flash chromatographyto afford 209.

H. Hydroxy diene 210.

A −78° C. solution of 209 (0.05 mmol) in CH₂Cl₂ (5 mL) is treated withdiisobutylaluminum hydride (0.5 mL, 1.0 M in toluene). The resultantsolution is stirred 10 min at −78° C. and 30 min at 0° C. The reactionis quenched with a saturated solution of sodium potassium tartrate (50mL) and the mixture is diluted with ether (60 mL) The organic layer isseparated, dried over magnesium sulfate, and concentrated in vacuo. Theresidue is purified by flash chromatography to afford 210.

I. Aldehyde 211.

To a −10° C. solution of 207 (1.3 mmol) and triethylamine (5.0 mmol) indichloromethane (3 mL) is added a solution of sulfur trioxide-pyridine(3.9 mmol) in dimethyl sulfoxide (5 mL). The mixture is stirred 1 h atroom temperature and diluted with ether (15 mL). The organic phase iswashed with aqueous sodium bisulfate (1 M, 10 mL), saturated aqueousbrine (4×10 mL), dried over magnesium sulfate, and concentrated invacuo. The residue is purified by flash chromatography to afford 211.

J. Tetraene 212.

A solution of diphenylallylphosphine (0.08 mL, 0.38 mmol) intetrahydrofuran (2 mL) is cooled to −78° C. and tert-butyllithium (0.14mL, 1.7 M in pentane) is added. The mixture is warmed to 0° C. for 30min, then recooled to −78° C. and treated with titanium (IV)isopropoxide (0.30 mmol). After 30 min, aldehyde 211 (0.30 mmol) isintroduced as a solution in tetrahydrofuran (2 mL). The resultantsolution is stirred at −78° C. for 15 min and at 0° C. for 1 h. Methyliodide (0.64 mmol) is added, and the reaction is warmed to roomtemperature for 12 h. The reaction mixture is diluted with ether (60mL), washed with aqueous sodium bisulfate (30 mL, 1.0 M), saturatedaqueous brine (30 mL), and is dried over magnesium sulfate andconcentrated in vacuo. The residue is purified by flash chromatographyto afford 212.

K. Aldehyde 213.

Oxalyl chloride (1.5 mmol) is-added dropwise to a −78° C. solution ofdimethyl sulfoxide (3 mmol) in dichloromethane (4 mL). After 15 min, a−78° C. solution of 212 (1 mmol) in dichloromethane (2 mL) is added viacanula. After an additional 15 min, diisopropylethylamine (4.5 mmol) isadded and the reaction is gradually warmed to room temperature over 1 hand quenched with aqueous sodium bisulfate. The mixture is diluted withether (50 mL) and is washed with water (2×30 mL), saturated aqueousbrine (2×30 mL), is dried over magnesium sulfate and concentrated invacuo. The residue is purified by flash chromatography to afford 213.

L. Ester 214.

To a −78° C. solution of (F₃CCH₂O)₂POCH₂CO₂Et (2 mmol) and 18-crown-6(2.4 mmol) in tetrahydrofuran (5 mL) is added potassiumbis(trimethylsilyl)amide (2 mmol) in tetrahydrofuran (2 mL). Theresultant solution is stirred 10 min at −78° C. and then treated withaldehyde 213 (1.2 mmol) in 4 mL of tetrahydrofuran. The reaction mixtureis warmed to 0° C. for 6-8 h and then quenched with saturated aqueousammonium chloride (10 mL). The aqueous layer is separated and extractedwith hexane (2×25 mL). The combined organics are dried over magnesiumsulfate and concentrated in vacuo. The residue is purified by flashchromatography to afford 214.

M. Alcohol 215.

To a solution of 214 (0.050 mmol) in dichloromethane (3 mL) at 0° C. isadded water (50 mL) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.018mmol). After 1 h, the reaction mixture is diluted with ethyl acetate (50mL), washed with saturated aqueous brine (3×25 mL), dried over magnesiumsulfate and concentrated in vacuo. The residue is purified by flashchromatography to afford 215.

N. Carbamate 216.

To a solution of 215 (0.010 mmol) in dichloromethane (2 mL) is addedtrichloroacetyl isocyanate (1.00 mmol). After 30 min, the reactionmixture is diluted with dichloromethane (4 mL) and neutral alumina (1 g)is added. The resultant suspension is stirred an additional 4 h. Thereaction mixture is filtered and the concentrated filtrate ischromatographed on silica gel to afford 216.

O. Triol 217.

A solution of 216 (0.010 mmol) in 48% hydrofluoric acid-acetonitrile(1:9, 2 mL) is stirred at ambient temperature. After 12 h, saturatedaqueous sodium bicarbonate (25 mL) is added and the mixture is extractedwith ethyl acetate (3×20 mL). The combined organics are dried overmagnesium sulfate and concentrated in vacuo. The residue is purified byflash chromatography to afford 217.

EXAMPLE 53 FIGS. 21 and 22

A. Hydroxy-oxazole 302.

A solution of oxazole (3 mmol) in tetrahydrofuran (15 mL) is cooled to−78° C. and treated with n-BuLi (3 mmol) in hexane. (see, Hodges, etal., J. Org. Chem. 1991, 56, 449). After 30 min at −78° C., previouslyprepared (see, Smith, et al., J. Am. Chem. Soc. 1995, 117, 12011)aldehyde 301 (2 mmol) is added in tetrahydrofuran (10 mL) and thereaction mixture is gradually allowed to warm to room temperature. After18-24 h, the reaction is quenched by addition of saturated aqueousammonium chloride (25 mL). The aqueous layer is separated and extractedwith ether (3×25 mL). The combined organics are dried over magnesiumsulfate and concentrated in vacuo. The residue is purified by flashchromatography to afford 302.

B. Tosylate 303.

A solution of 302 (1.0 mmol) in anhydrous pyridine (10 mL) at 0° C. istreated with p-toluenesulfonyl chloride (286 mg, 1.5 mmol). The mixtureis allowed to warm to room temperature for 4-6 h. The pyridine isremoved in vacuo and the residue is purified by flash chromatography toafford tosylate 303.

C. Reduction product 304.

To a 0° C. solution of tosylate 303 (0.5 mmol) in tetrahydrofuran (2 mL)is added lithium triethylborohydride (2 mmol) as a solution intetrahydrofuran (1.0 M). The resultant solution is warmed to roomtemperature for 2-4 h and then quenched with water (1 mL) and dilutedwith ether (25 mL). The ethereal layer is washed with saturated aqueousbrine (2×10 mL), dried over magnesium sulfate, and concentrated invacuo. The residue is purified by flash chromatography to afford 304.

D. Lactol 305.

To a solution of 304 (0.1 mmol) in tetrahydrofuran-acetonitrile (15 mL,2:1) is added phosphate buffer (pH 7, 5 mL) and mercury (II) chloride(1.0 mol). The resultant mixture is stirred 1 h at room temperature. Thereaction mixture is diluted with ether (100 mL) and washed withsaturated aqueous brine (2×50 mL), dried over magnesium sulfate andconcentrated in vacuo. The residue is purified by flash chromatographyto afford 305 as a mixture of a and f anomers.

E. Lactone 306.

To a solution of 305 (0.070 mmol) in dimethyl sulfoxide (10 mL) is addedacetic anhydride (2 mL). After 2 days at room temperature, the mixtureis diluted with ether (100 mL) and washed with saturated aqueous sodiumbicarbonate (50 mL), saturated aqueous brine (50 mL), dried overmagnesium sulfate and concentrated in vacuo. The residue is purified byflash chromatography to afford 306.

F. Alcohol 307.

To a solution of 306 (0.050 mmol) in dichloromethane (3 mL) at 0° C. isadded water (50 mL) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.018mmol). After 1 h, the reaction mixture is diluted with ethyl acetate (50mL) ) washed with saturated aqueous brine (3×25 mL), dried overmagnesium sulfate and concentrated in vacuo. The residue is purified byflash chromatography to afford 307.

G. Carbamate 308.

To a solution of 307 (0.010 mmol) in dichloromethane (2 mL) is addedtrichloroacetyl isocyanate (1.00 mmol). After 30 min, the reactionmixture is diluted with dichloromethane (4 mL) and neutral alumina (1 g)is added. The resultant suspension is stirred an additional 4 h. Thereaction mixture is filtered and the concentrated filtrate ischromatographed on silica gel to afford 308.

H. Tetrol 309.

A solution of 308 (0.010 mmol) in 48% hydrofluoric acid-acetonitrile(1:9, 2 mL) is stirred at ambient temperature. After 12 h, saturatedaqueous sodium bicarbonate (25 mL) is added and the mixture is extractedwith ethyl acetate (3×20 mL). The combined organics are dried overmagnesium sulfate and concentrated in vacuo. The residue is purified byflash chromatography to afford 309.

EXAMPLE 54

As shown in FIG. 23, a solution of 402 (10.5 mg, 10.4 mmol) in 48%HF—CH₃CN (1:9, 1.0 mL) is stirred at room temperature for 12 hr. Thereaction is quenched by saturated NaHCO₃ (5.0 mL). The mixture isextracted with ethyl acetate (3×10 mL). The combined organic phase isthen washed with brine (5.0 mL), dried over MgSO₄, concentrated invacuo. The residue is purified by flash chromatography to afford 401.

EXAMPLE 55 FIG. 24

A. PMB-ether 503

ZnCl₂(1.32 g, 9.69 mmol) is dried at 160° C. under vacuum overnight andthen treated with a solution of iodide 502 (2.46 g, 9.59 mmol) in dryEt₂O (50 mL). The mixture is stirred at room temperature until most ofthe ZnCl₂ is dissolved and then cooled to −78° C. t-BuLi (1.7M inpentane, 17.0 mL) is added over 30 min, and the resultant solution isstirred an additional 15 min, warmed to room temperature, and stirredfor 1 hr. The solution is added by cannula to a mixture of iodoolefin B(see, Smith, et al., J. Am. Chem. Soc. 1995, 117, 12011) (3.21 g, 6.19mmol) and Pd(PPh₃)₄ (364.2 mg, 0.315 mmol) The mixture is covered withaluminum foil, stirred overnight, and then diluted with ethylacetate(100 mL), washed with brine (2×100 mL), dried over MgSO₄,filtered and concentrated in vacuo. The residue is purified by flashchromatography to afford 503.

B. Phosphonium Salt 504

A solution of alcohol 503 (1.70 g, 3.26 mmol) in CH₂Cl₂ (28 mL) iscooled to 0° C. and treated with water (1.3 mL) and2,3-dichloro-5,6-dicyano-1,4-benzoquinone (774 mg, 3.41 mmol). Themixture is stirred at 0° C. for 5 hr, diluted with CH₂Cl₂ (20 mL), driedover MgSO₄, and filtered through a column of silica gel. Followingconcentration in vacuo, the residue is dissolved in ethanol (50 mL) atroom temperature, and excess sodium borohydride is added. After 30 min,the reaction is cooled to 0° C., quenched with saturated aqueous NH₄Cl(50 mL), and concentrated. The residue is then dissolved in CH₂Cl₂(90mL), and the solution is washed with water, dried over MgSO₄, filteredand concentrated in vacuo. The residue is purified by flashchromatography to afford an alcohol A solution of this alcohol (400 mg,1.0 mmol) in dry benzene/ether (1:2, 50 mL) is treated withtriphenylphosphine (923 mg, 3.6 mmol) and imidazole (273 mg, 4.0 mmol).After all of the imidazole dissolved, iodine (761 mg, 3.0 mmol) is addedwith vigorous stirring of the reaction mixture. The mixture is stirred 2h further and then treated with triethylamine (4 mL) The resultantsolution is diluted with CH₂Cl₂ (50 mL) and washed with saturatedaqueous Na₂S₂O₃(100 mL), saturated aqueous NaHCO₃(100 mL), and brine(2×100 mL). The organic phase is dried over MgSO₄, filtered andconcentrated in vacuo. Filtration though silica gel to removetriphenylphosphine oxide, affords an iodide. The iodide was mixed withdiisopropylethylamine (0.6 mL, 3.44 mmol) and triphenylphosphine (4.94g, 18.8 mmol). The mixture is heated at 80° C. for 24 hr, cooled to roomtemperature, and washed with hexane (2×50 mL). The product is isolatedby flash chromatography to afford 504.

C. Coupled product 505.

Phosphonium salt 504 (386 mg, 0.5 mmol) is dried azeotropically with drybenzene and heated at 50° C. under vacuum for 3 hr before use. It isthen dissolved in tetrahydrofuran (3.0 mL). Sodiumbis(trimethylsilyl)amide (1.0 M in tetrahydrofuran, 0.48 mL, 0.48 mmol)is added at −78° C., and the mixture is stirred for 25 min and thenrecooled to −78° C. A solution of aldehyde C (see, Smith, et al., J. Am.Chem. Soc. 1995, 117, 12011) (147 mg, 0.30 mmol) in tetrahydrofuran (1.5mL) is added, and the mixture is stirred for 10 min at −78° C., and 2 hrat room temperature. The reaction is quenched with saturated aqueousNH₄Cl(4.0 mL), the resultant mixture is extracted with ether (120 mL),and the ether layer is washed with water (100 mL) and brine(100 mL),dried over MgSO₄, filtered and concentrated in vacuo. Flashchromatography provides olefin 505.

D. Lactone 506.

To a solution of 505 (200 mg, 0.23 mmol) in tetrahydrofuran-acetonitrile(10 mL, 2:1) is added a phosphate buffer solution (pH=7.0, 3.3 mL), andHgCl₂(1.3 g). The suspension is stirred at room temperature for 40 min,then diluted with ether (150 mL), washed with brine (2×70 mL), driedover MgSO₄, and concentrated in vacuo. Flash chromatography provides amixture of lactols as α/β anomers. This material is used directly in thenext oxidation: Under argon, to a solution of lactols indimethylsulfoxide (5.0 mL) is added acetic anhydride (1.0 mL). After 2days at room temperature, the mixture is diluted with ether (150 mL),washed with saturated NaHCO₃(150 mL), brine (150 mL)), dried over MgSO₄,and concentrated in vacuo. Flash chromatography affords a lactone. Asolution of the lactone (160 mg, 0.20 mmol) in methanol (4 mL) istreated with pyridinium p-toluenesulfonate (10 mg) and stirred at 40° C.for 30 min. The mixture is diluted with ether (80 mL) and washedsuccessively with saturated aqueous NaHCO₃ solution (90 mL) and brine(40 mL), and then dried over MgSO₄. The organic solution is concentratedin vacuo, and the residue is passed through a column of silica gel toprovide alcohol 506.

E. Acid 507.

To a solution of alcohol 506 (140 mg, 0.19 mmol) in dimethylformamide(5.0 mL), is added pyridinium dichromate (210 mg, 0.55 mmol). Thereaction mixture is stirred at room temperature for 5 hr, and dilutedwith water (120 mL). The mixture is extracted with ether (3×15 mL). Theorganic solutions are combined and washed with brine (40 mL), and driedover MgSO₄. Then it is concentrated in vacuo to give a residue, which ispurified by flash chromatography to afford carboxylic acid 507.

F. Amino-amide 508.

To a solution of 507 (60.0 mg, 78.1 mmol) and D-leucine hydrochloride(26.0 mg, 0.16 mmol) in CH₂Cl₂ (3 mL) is added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 23 mg,0.12 mmol) and 1-hydroxybenzotriazole (21.0 mg, 0.14 mmol), followed bydiisopropylamine (40 mL, 0.23 mmol). The mixture is stirred at roomtemperature overnight before addition of 5% KHSO₄ solution. Theresulting mixture is extracted with ethyl acetate (30 mL). The organiclayer is washed with brine (20 mL) and dried over MgSO₄, and thenconcentrated in vacuo. The residue is purified by column chromatographyto afford 508.

G. Analog 501.

A solution of 508 (52 mg, 59 mmol) in 48% HF-acetonitrile(1:9, 1.0 mL)is stirred at room temperature for 12 hr. The reaction is quenched bysaturated NaHCO₃(5.0 mL). The mixture is extracted with ethyl acetate(3×10 mL). The combined organic phase is then washed with brine (5.0mL), dried over MgSO₄, and concentrated in vacuo. Flash chromatographyprovides 501.

EXAMPLE 56 FIG. 25.

A. Diene 603.

Phosphonium salt 15 (98.0 mg, 0.092 mmol) is dried azeotropically withdry benzene and heated at 50° C. under vacuum for 3 hr before use. It isthen dissolved in tetrahydrofuran (0.7 mL). Sodiumbis(trimethylsilyl)amide (1.0 M in tetrahydrofuran, 86 mL, 0.0855 mmol)is added at −78° C., and the mixture is stirred for 20 min and thenrecooled to −78° C. A solution of aldehyde 602 (13 mg, 60 mmol) intetrahydrofuran (300 mL) is added, and the mixture is stirred for 10 minat −78° C., and 2 hr at room temperature. The reaction is quenched withsaturated aqueous NH₄Cl (1.0 mL). The resultant mixture is extractedwith ether (30 mL), and the ether layer is washed with water (30 mL) andbrine (30 mL), dried over MgSO₄, filtered and concentrated in vacuo.Flash chromatography provides the coupled product.

A solution of the olefin (39 mg, 44 mmol) in CH₂Cl₂ is cooled to −78°C., diisobutylaluminum hydride (1.0 M in toluene, 440 mL, 0.40 mmol) isadded dropwise over 5 min, and the resultant solution is stirred for 10min at −78° C. and 30 min at 0° C. The reaction is quenched with asaturated solution of Rochelle's salt, and the mixture is diluted withether (60 mL), washed with Rochelle solution, and brine(30 mL each),dried over MgSO₄, filtered and concentrated in vacuo. Flashchromatography provides alcohol 603.

B. Alkane 604.

To a solution of alcohol 603 (82 mg, 0.93 mmol) in pyridine (1.5 mL) at0° C. is added p-toluenesulfonyl chloride(26.6 mg, 0.14 mmol) withstirring. After 3 hr, the reaction mixture is concentrated in vacuo. Theresidue is purified by column chromatography to give a tosylate. To asolution of this tosylate (94 mg, 0.91 mmol) in ether (5 mL) is addedlithium diisopropylcuprate (Pr₂CuLi) (ca. 0.5 M in ether, 10 mL, excess.The resultant solution is stirred for 8 hr and then quenched withsaturated aqueous solution of NH₄Cl (50 mL). Stirring is continued foran additional 2 h. The organic phase is separated and washed with NH₄Clsolution (20 mL), dried over MgSO₄, and concentrated in vacuo. Flashchromatography provides 604.

C. Enone 605.

A solution of 604 (75 mg, 83 mmol) in methanol (2 mL) is treated withpyridinium p-toluenesulfonate (ca.4 mg) and stirred at 40° C. for 30min. The mixture is diluted with ether (20 mL) and washed successivelywith saturated aqueous NaHCO₃ solution (25 mL) and brine (10 mL), andthen dried over MgSO₄. The organic solution is concentrated in vacuo,and the residue is passed through a column of silica gel to provide analcohol. To a solution of the alcohol (62.0 mg, 68.2 mmol) in benzene(2.0 mL) is added manganese(IV) oxide (100 mg, 1.15 mmol). Afterstirring for 8 h at room temperature, the reaction mixture is filteredthrough a pad of celite. The filtrate is concentrated in vacuo. Flashchromatography of the residue affords α,β-unsaturated ketone 605.

D. Triol 606.

A solution of the α,β-unsaturated ketone 605 (45 mg, 56 mmol) in CH₂Cl₂(2 mL) is cooled to 0° C. and treated with water (0.1 mL) and2,3-dichloro-5,6-dicyano-1,4-benzoquinone (15 mg, 66 mmol). The mixtureis stirred at 0° C. for 5 hr, diluted with CH₂Cl₂ (15 mL), dried overMgSO₄, and filtered through a column of silica gel. Followingconcentration in vacuo, the residue is used for next step withoutfurther purification. A solution of the crude alcohol in 48%HF-acetonitrile(1:9, 1.0 mL) is stirred at room temperature for 12 hr.The reaction is quenched by saturated NaHCO₃ (5.0 mL). The mixture isextracted with ethyl acetate(3×10 mL). The combined organic phase isthen washed with brine (5.0 mL), dried over MgSO₄, concentrated invacuo. The residue is purified by flash chromatography to afford 601.

EXAMPLE 57 FIG. 26

A. Alkane 702

To a solution of iodide A (300 mg, 0.54 mmol) in ether (5 mL) is addedlithium dibutylcuprate (Bu₂CuLi) (ca. 0.5 M in ether, 5.4 mL, excess) at−25° C. The resultant solution is stirred for 8 hr and then quenchedwith saturated aqueous NH₄Cl (50 mL). Stirring is continued for another2 hr and the organic phase is separated. The organic solution is washedwith NH₄Cl solution (20 mL) and dried over MgSO₄, and concentrated invacuo. Flash chromatography provides 702.

B. Alcohol 703.

A solution of 702 (240 mg, 0.50 mmol) in CH₂Cl₂ (6.0 mL) is cooled to−78° C. Diisobutylaluminum hydride (1.0 M in toluene, 1.50 mL, 1.50mmol) is added dropwise over 5 min, and the resultant solution isstirred for 10 min at −78° C. and 30 min at 0° C. The reaction isquenched with a saturated solution of Rochelle's salt, and the mixtureis diluted with ether (60 mL), washed with Rochelle solution, and brine(30 mL each), dried over MgSO₄, filtered and concentrated in vacuo.Flash chromatography provides alcohol 703.

C. Iodide 704

A solution of alcohol 703 (210 mg, 0.44 mmol) in dry benzene/ether (1:2,5 mL) is treated with triphenylphosphine (420 mg, 1.6 mmol) andimidazole (123 mg, 1.8 mmol). After all of the imidazole dissolved,iodine (335 mg, 1.32 mmol) is added with vigorous stirring. The mixtureis stirred for 2 h and then treated with triethylamine (1.8 mL). Theresultant solution is diluted with CH₂Cl₂ (22 mL) and washed withsaturated aqueous Na₂S₂O₃ (40 mL), saturated aqueous NaHCO₃ (40 mL), andbrine (2×40 mL) The organic phase is dried over MgSO₄, filtered andconcentrated in vacuo. The residue is purified by flash chromatographyto afford iodide 704.

D. Phosphonium salt 705.

The iodide 704 is mixed with triphenylphosphine (2.17 g, 8.27 mmol) andthe mixture is heated at 80° C. for 24 hr, cooled to room temperature,and washed with hexane (2×20 mL). Flash chromatography providesphosphonium salt 705.

E. Alkene 707.

A solution of 705 (260 mg, 0.30 mmol) in tetrahydrofuran (6.0 mL) iscooled to −10° C. and a solution of n-butyl lithium (1.0 M in hexane,0.29 mL, 0.29 mmol) is introduced dropwise over 5 min. The resultantsolution is stirred for 50 min at room temperature and then the mixtureis recooled to −78° C. and aldehyde 706 (39 mg, 0.3. mmol) is added asolution in tetrahydrofuran (1.5 mL). The mixture is stirred for 10 minat −78° C., and 1 hr at 0° C. The reaction is quenched with saturatedaqueous NH₄Cl (1.0 mL) and the resultant mixture is extracted with ether(30 mL). The ether layer is washed with water (30 mL) and brine (30 mL),dried over MgSO₄, filtered and concentrated in vacuo. The residue ispurified by flash chromatography to afford olefin 707 (149 mg, 85%yield).

F. Diol 708.

Acetonide 707 (147 mg, 0.25 mmol) is dissolved in 80% aqueous aceticacid (2.5 mL) at room temperature. The reaction mixture is stirred for 4hr at room temperature and then diluted with water (20 mL). The mixtureis extracted with ethyl acetate (2×5 mL). The combined organic layersare washed with saturated NaHCO₃ solution, and brine (10 mL each), andthen dried over MgSO₄. The organic solution is concentrated in vacuo,and the residue is flash chromatographed over silica gel to afford diol708.

G. Tosylate 709.

To a solution of diol 708 (134 mg, 0.25 mmol) in pyridine (2 mL) isadded p-toluenesulfonyl chloride(52 mg, 0.27 mmol). After 3 hr, thereaction mixture is diluted with ether (30 mL), and washed with ice cold1 M hydrochloric acid (60 mL), saturated NaHCO₃ solution (20 mL), andbrine (20 mL) and then concentrated in vacuo. The residue is purified bycolumn chromatography to give a monotosylate 709.

H. Epoxide 710.

A solution of tosylate 709 (145 mg, 0.21 mmol) in methanol (3.0 mL) isadded potassium carbonate (10 mg) at room temperature. The mixture isstirred for 20 min, and then diluted with water (60 mL) and extractedwith ethyl acetate (2×20 mL). The combined organic layers are washedwith brine and concentrated in vacuo. Flash chromatography providesepoxide 710.

I. Alcohol 711.

To a solution of 710 (41 mg, 79 mmol) in CH₂Cl₂ (3.0 mL) at 0° C. isadded water (0.15 mL) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (60mg, 0.26 mmol). The mixture is stirred at 0° C. for 5 hr, diluted withCH₂Cl₂ (15 mL), dried over MgSO₄, and filtered through a column ofsilica gel. Following concentration in vacuo, the crude 711 is usedwithout further purification.

J. Carbamate 712.

To a solution of 711 (8.7 mg, 22 mmol) in CH₂Cl₂ (1.0 mL) is addedtrichloroacetyl isocyanate (0.20 mL, 1.7 mmol) at room temperature.After 30 min, the mixture is diluted with CH₂Cl₂(20 mL), and someneutral Al₂O₃ (500 mg) is added. The mixture is then stirred at roomtemperature for 2 hr, then filtered though a short column of silica gel,and concentrated in vacuo. The residue is purified by flashchromatography to afford 712.

K. Hydroxy-urethane 701.

A solution of 712 (6.0 mg, 14 mmol) in 48% HF-acetonitrile (1:9, 1.0 mL)is stirred at room temperature for 12 hr. The reaction is quenched bysaturated NaHCO₃ (5.0 mL). The mixture is extracted with ethyl acetate(3×10 mL). The combined organic phase is then washed with brine (5.0mL), dried over MgSO₄, and concentrated in vacuo. The residue ispurified by flash chromatography afford 701.

EXAMPLE 58 FIGS. 27 and 28

A. Iodide 802.

A solution of alcohol 16 (see, Smith, et al., J. Am. Chem. Soc. 1995,117, 12011) (410 mg, 0.360 mmol) in dry benzene/ether (1:2, 10 mL) istreated with triphenylphosphine (378 mg, 1.44 mmol) and imidazole (111mg, 1.62 mmol). After complete dissolution of the imidazole, iodine (301mg, 1.19 mmol) is added with vigorous stirring. The reaction mixture isstirred 2 h and then treated with triethylamine (1.7 mL). The resultantsolution is diluted with CH₂Cl₂ (30 mL) and washed with saturatedaqueous Na₂S₂O₃ (40 mL), saturated aqueous NaHCO₃ (40 mL), and brine(2×40 mL). The organic phase is dried over MgSO₄, filtered andconcentrated in vacuo. Purification of the residue by flashchromatography affords iodide 802.

B. Phosphonium salt 803.

To a solution of iodide 802 (410 mg, 0.325 mmol) in benzene (20 mL) isadded triphenylphosphine(1.00 g, 3.81 mmol). The mixture is heated at80° C. for 24 hr. cooled to room temperature, and concentrated in vacuo.The residue is washed with hexane (2×20 mL). Flash chromatographyaffords phosphonium salt 803.

C. Alkene 805

A solution of 803 (460 mg, 0.30 mmol) in tetrahydrofuran (9.0 mL) iscooled to −10° C. A solution of n-butyl lithium (1.0 M in hexane, 0.29mL, 0.29 mmol) is added dropwise over 5 min, and the resultant solutionis stirred for 50 min at room temperature. Then the mixture is recooledto -78° C. and a solution of aldehyde 804 (39 mg, 0.3 mmol) intetrahydrofuran (1.5 mL) is added. The mixture is stirred for 10 min at−78° C., and 1 hr at 0° C. The reaction is quenched with saturatedaqueous NH₄Cl (20 mL), the resultant mixture is extracted with ether (40mL), and the ether layer is washed with water (30 mL) and brine (30 mL),dried over MgSO₄, filtered and concentrated in vacuo. Flashchromatography of the residue affords 805.

D. Diol 806

Acetonide 805 (280 mg, 0.22 mmol) is dissolved in 80% aqueous aceticacid (3.5 mL) at room temperature. The reaction mixture is stirred for 4hr at room temperature and then diluted with water (40 mL). The mixtureis extracted with ethyl acetate (2×10 mL). The combined organic layersare washed with saturated NaHCO₃ solution, and brine (10 mL each), andthen dried over MgSO₄. The organic solution is concentrated in vacuo,and the residue is flash chromatographed over silica gel to afford diol806.

E. Tosylate 807.

To a solution of diol 806 (235 mg, 0.19 mmol) in pyridine (2 mL) at 0°C. is added p-toluenesulfonyl chloride (45 mg, 0.23 mmol). After 3 hr,the reaction mixture is diluted with ether (30 mL), and washed with icecold 1 M hydrochloric acid (30 mL), saturated NaHCO₃ solution (20 mL),and brine (20 mL) and then concentrated in vacuo. The residue ispurified by column chromatography to give a monotosylate 807.

F. Epoxide 808.

To a solution of tosylate 807 (187 mg, 0.21 mmol) in methanol (3.0 mL)is added potassium carbonate (10 mg) at room temperature. The mixture isstirred for 20 min, and then diluted with water (60 mL) and extractedwith ethyl acetate (2×20 mL). The combined organic layers were washedwith brine and concentrated in vacuo. Flash chromatography providesepoxide 808.

G. Lactone 809.

To a solution of 808 (110 mg, 93 mmol) in tetrahydrofuran-acetonitrile(10 mL, 2:1) is added a phosphate buffer solution (pH=7.0, 3.5 mL)), andHgCl₂ (2.3 g). The suspension is stirred at room temperature for 40 min,then diluted with ether (30 mL), washed with brine (2×30 mL), dried overMgSO₄, and concentrated in vacuo. Flash chromatography affords thelactol as an α/β anomeric mixture. This material is used directly in thenext oxidation: Under argon atmosphere, a solution of the lactols indimethylsulfoxide (3.0 mL) is treated with acetic anhydride (0.60 mL).After 2 days at room temperature, the mixture is diluted with ether (50mL), washed with saturated NaHCO₃ (30 mL), brine (30 mL), dried overMgSO₄, and concentrated in vacuo. Flash chromatography provides 809.

H. Alcohol 810.

To a solution of 809 (90 mg, 79 mmol) in CH₂Cl₂ (3.0 mL) at 0° C. isadded water (0.15 mL) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (60mg, 0.26 mmol). The mixture is stirred at 0° C. for 5 hr, diluted withCH₂Cl₂ (15 mL), dried over MgSO₄, and filtered through a column ofsilica gel. Following concentration in vacuo, the crude 810 is used inthe next reaction without further purification.

I. Carbamate 811

To a solution of 810 (22 mg, 22 mmol) in CH₂Cl₂ (1.0 mL) is addedtrichloroacetyl isocyanate (0.20 mL, 1.7 mmol) at room temperature.After 30 min, the mixture is diluted with CH₂Cl₂(20 mL), and someneutral Al₂O₃ (500 mg) is added. The mixture is then stirred at roomtemperature for 2hr, then filtered though a short column of silica gel,and concentrated in vacuo. Flash chromatography affords 811.

J. Epoxide analog 812.

A solution of 811 (15 mg, 14 mmol) in tetrahydrofuran (1.0 mL) is cooledto 0° C., and treated with a 1.0 M solution of tetrabutylammoniumfluoride in tetrahydrofuran (0.14 mL, 0.14 mmol). The reaction mixtureis stirred for 2 hr, and diluted with water (20 mL) The mixture isextracted with ethyl acetate (3×10 mL). The combined organic phase isthen washed with brine (10 mL), dried over MgSO₄, concentrated in vacuo.Flash chromatography affords 801.

EXAMPLE 59 FIG. 29

A. Alcohol 903.

Phosphonium salt 15 (98.0 mg, 0.092 mmol) is dried azeotropically withdry benzene and heated at 50° C. under vacuum for 3 hr before use. It isthen dissolved in tetrahydrofuran (0.7 mL). Sodiumbis(trimethylsilyl)amide (1.0 M in tetrahydrofuran, 86 mL, 0.0855 mmol)is added at −78° C., and the mixture is stirred for 20 min and thenrecooled to −78° C. A solution of aldehyde 902 (60 mmol) intetrahydrofuran (300 mL) is added, and the mixture is stirred for 10 minat −78° C., and 2 hr at room temperature. The reaction is quenched withsaturated aqueous NH₄Cl (1.0 mL). The resultant mixture is extractedwith ether (30 mL), and the ether layer is washed with water (30 mL) andbrine (30 mL), dried over MgSO₄, filtered and concentrated in vacuo.Flash chromatography provides an olefin. A solution of the olefin (44mmol) in CH₂Cl₂ is cooled to −78° C. Diisobutylaluminum hydride (1.0 Min toluene, 440 mL, 0.40 mmol) is added dropwise over 5 min, and theresultant solution is stirred for 10 min at −78° C. and 30 min at 0° C.The reaction is quenched with a saturated solution of Rochelle's salt,and the mixture is diluted with ether (60 mL), washed with Rochellesolution, and brine (30 mL each), dried over MgSO₄, filtered andconcentrated in vacuo. Flash chromatography provides alcohol 903.

B. Diene 905.

A solution of 903 (0.012 mmol) and Et₃N (42 mL, 0.30 mmol) in CH₂Cl₂(2.0 mL) is cooled to 0° C. and a solution of SO₃-pyridine complex (40mg, 0.251 mmol) in dimethylsulfoxide (0.6 mL) is added. The mixture isstirred at 0° C. for 45 min and then diluted with ethyl acetate (30 mL),washed with aqueous NaHSO₄ (1.0 M, 30 mL) and brine (2×30 mL), driedover MgSO₄, and concentrated in vacuo. Flash chromatography affords analdehyde. A solution of allyldiphenylphosphine 904 (0.19 mmol) intetrahydrofuran (1.0 mL) is cooled to −78° C. and t-butyl lithium (1.7 Min pentane, 0.122 mmol) is added. The mixture is stirred at 0° C. for 30min, recooled to −78° C. and treated titanium tetra-I-propoxide (0.15mmol). After 30 min, a cold (−78° C.) solution of the aldehyde (0.26mmol) in tetrahydrofuran (1.0 mL) is introduced via cannula, and themixture is stirred 10 min further at −78° C. and at 0° C. for 1 hr.Iodomethane (0.32 mmol) is added, and the reaction is maintained at 0°C. for 30 min, warmed to room temperature, protected from light, andstirred overnight. The reaction mixture is diluted with ether (30 mL),washed with 1.0 M aqueous NaHSO₄ and brine (30 mL each), dried overMgSO₄, concentrated in vacuo. Flash chromatography affords diene 905.

C. Glycoside 908.

A solution of 905 (83 mmol) in methanol (2 mL) is treated withpyridinium p-toluenesulfonate (ca.4 mg) and stirred at 40° C. for 30min. The mixture is diluted with ether (20 mL) and washed successivelywith saturated aqueous NaHCO₃ solution (25 mL) and brine (10 mL), andthen dried over MgSO₄. The organic solution is concentrated in vacuo,and the residue is passed through a column of silica gel to give analcohol.

To a solution of glycosyl bromide 906 (75 mmol) in CH₂Cl₂(2.0 mL) isadded HgBr₂ (7 mmol) and powdered molecular sieves (4 Å, 50 mg) andstirred for 60 min at room temperature. The mixture is then cooled to 0°C., and the alcohol (74 mmol) prepared above is added in CH₂Cl₂ (0.7mL). The resultant mixture is stirred 6 hr at 0° C. and then warmed toroom temperature and diluted with CH₂Cl₂ (10 mL), and filtered through apad of celite. The filtrate is washed with aqueous KI solution, anddried over MgSO₄. The organic solution is concentrated in vacuo, and theresidue is passed through a column of silica gel to give an anomericmixture of glycosides 908.

D. Triol 901.

To a solution of 908 (79 mmol) in CH₂Cl₂ (3.0 mL) at 0° C. is addedwater (0.15 mL) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (60 mg,0.26 mmol). The mixture is stirred at 0° C. for 5 hr, diluted withCH₂Cl₂ (15 mL), dried over MgSO₄, and filtered through a column ofsilica gel. Following concentration in vacuo, the crude alcohol is usedfor next step without further purification. To a solution of the alcohol(22 mmol) in CH₂Cl₂ (1.0 mL) is added trichloroacetyl isocyanate (0.20mL, 1.7 mmol) at room temperature. After 30 min, the mixture is dilutedwith CH₂Cl₂(20 mL), and some neutral Al₂O₃ (500 mg) is added. Themixture is then stirred at room temperature for 2 hr, then filteredthough a short column of silica gel, and concentrated in vacuo. Flashchromatography affords a carbamate. A solution of the carbamate (14mmol) in 48% HF-acetonitrile (1:9, 1.0 mL) is stirred at roomtemperature for 12 hr. The reaction is quenched by saturated NaHCO₃ (5.0mL). The mixture is extracted with ethyl acetate (3×10 mL). The combinedorganic phase is then washed with brine(5.0 mL), dried over MgSO₄,concentrated in vacuo. Flash chromatography affords 901.

EXAMPLE 60 FIG. 30

A. Olefin 1001

A solution of model phosphonium salt (0.0917 mmol) in THF (700 mL) iscooled to −78° C. and treated with NaHMDS (1.0 M in THF, 85.5 mL, 0.0855mmol). The mixture is stirred for 20 min at 0° C., recooled to −78° C.and aldehyde C (0.0570 mmol) in THF (300 mL) is added. After 10 min at−78° C. and 2 h at room temperature, the mixture is quenched withsaturated aqueous NH₄Cl (1.0 mL) and extracted with ether (30 mL). Theether solution is washed with water, brine (30 mL each), dried overMgSO₄, filtered and concentrated. Flash chromatography provides olefin1001.

B. Lactone 1002

A solution of olefin 1001 (0.00597 mmol) in THF/CH₃CN (2:1, 1.50 mL) istreated with pH 7.0 phosphate buffer (500 mL) and HgCl₂ (215 mg). Thesuspension is stirred at room temperature for 40 min, diluted with ether(30 mL), washed with brine (2×30 mL), dried over MgSO₄, filtered andconcentrated. Pipette flash chromatography (5% ethyl acetate/hexane)provides a mixture of lactols as a colorless oil which is furthertreated with DMSO (1.0 mL) and Ac₂O (200 mL) at room temperature for 2days. The mixture is diluted with ether (30 mL), washed with saturatedNaHCO₃ (30 mL), brine (30 mL)), dried over MgSO₄, filtered andconcentrated. Flash chromatography provides lactone 1002.

C. Model Compound 1003

A solution of olefin 1002 (5.5 mmol) in 48% HF—CH₃CN (1:9, 1.0 mL) isstirred at room temperature for 12 h, then quenched with saturatedaqueous NaHCO₃ (5.0 mL). The mixture is extracted with ethyl acetate(3×10 mL). The combined organic extracts are washed with brine (5.0 mL),dried over MgSO₄, filtered and concentrated. Pipette flashchromatography (gradient elution, 1:30 to 1:6 MeOH/CHCl₃) provides 1003.

EXAMPLE 61 FIGS. 31 and 32

I. General Procedure for Synthesis of hydroxy aldehydes 1104.

A. TBS ether 1102a

A solution of bromide 1101a (see, Jacquesy, et al., Tetrahedron 1981,37, 747) (20 mmol) in ether (40 mL) is added slowly to a −78° C.solution of tert-butyllitium (40 mmol, 1.7 M in pentane). After 1 h at−78° C., the cold solution is transferred to a suspension of copper (I)iodide (10 mmol) in ether at 0° C.. After an additional 30 min at 0° C.,a solution of benzyl (S)-(+)-glycidyl ether (9 mmol) in ether (20 mL) isadded and the reaction is allowed to warm to room temperature. After18-24 h, the reaction is quenched by the addition oftert-butyldimethylsilyl triflate (10 mmol). The reaction mixture ispoured into saturated aqueous sodium bicarbonate (100 mL). The aqueouslayer is separated and extracted with ether (2×50 mL). The combinedorganics are washed with saturated aqueous brine (50 mL), dried overmagnesium sulfate and concentrated in vacuo. The residue is purified byflash chromatography to afford 1102a.

B. Alcohol 1103a.

To a solution of 1102a (6 mmol) in ethyl acetate-ethanol (8:1, 90 mL) isadded palladium on carbon (10% wet, 500 mg). The mixture is stirredunder hydrogen atmosphere for 3-6 h, then filtered and concentrated invacuo. The residue is purified by flash chromatography to afford 1103a.

C. Aldehyde 1104a.

Oxalyl chloride (1.5 mmol) is added dropwise to a −78° C. solution ofdimethyl sulfoxide (3 mmol) in dichloromethane (4 mL). After 15 min, a−78° C. solution of 1103a (1 mmol) in dichloromethane (2 mL) is addedvia canula. After an additional 15 min, diisopropylethylamine (4.5 mmol)is added and the reaction is gradually warmed to room temperature over 1h and quenched with aqueous sodium bisulfate. The mixture is dilutedwith ether (50 mL) and is washed with water (2×30 mL), saturated aqueousbrine (2×30 mL), is dried over magnesium sulfate and concentrated invacuo. The residue is purified by flash chromatography to afford 1104a.

II. General Procedure for the Conversion of 1104 to arene analog 1111:

A. Diene 1105.

Phosphonium salt 15 (see, Smith, et al., J. Am. Chem. Soc. 1995, 117,12011) (0.2 mmol) is dissolved in anhydrous tetrahydrofuran (2 mL) andchilled to 0° C. A solution of sodium bis(trimethylsilyl)amide (0.2mmol, 1.0 M in tetrahydrofuran) is added and the reaction mixture isstirred 30 min at 0° C. After cooling to −78° C., a solution of aldehyde1104 (0.1 mmol) in tetrahydrofuran (2 mL) is added and the mixture isstirred 10 min at −78° C. and 2 h at room temperature. Saturated aqueousammonium chloride (2 mL) is added and the resultant mixture is extractedwith ether (3×20 mL). The ethereal layer is washed with water (2×25 mL)and saturated aqueous brine (25 mL), dried over magnesium sulfate andconcentrated in vacuo. The residue is purified by flash chromatographyto afford 1105.

B. Hydroxy diene 1106.

A −78° C. solution of 1105 (0.05 mmol) in CH₂Cl₂ (5 mL) is treated withdiisobutylaluminum hydride (0.5 mL, 1.0 M in toluene). The resultantsolution is stirred 10 min at −78° C. and 30 min at 0° C. The reactionis quenched with a saturated solution of sodium potassium tartrate (50mL) and the mixture is diluted with ether (60 mL). The organic layer isseparated, dried over magnesium sulfate, and concentrated in vacuo. Theresidue is purified by flash chromatography to afford 1106.

C. Aldehyde 1107.

Oxalyl chloride (1.5 mmol) is added dropwise to a −78° C. solution ofdimethyl sulfoxide (3 mmol) in dichloromethane (4 mL). After 15 min, a−78° C. solution of 1106 (1 mmol) in dichloromethane (2 mL) is added viacanula. After an additional 15 min, diisopropylethylamine (4.5 mmol) isadded and the reaction is gradually warmed to room temperature over 1 hand quenched with aqueous sodium bisulfate. The mixture is diluted withether (50 mL) and is washed with water (2×30 mL), saturated aqueousbrine (2×30 mL), is dried over magnesium sulfate and concentrated invacuo. The residue is purified by flash chromatography to afford 1107.

D. Tetraene 1108.

A solution of diphenylallylphosphine (0.08 mL, 0.38 mmol) intetrahydrofuran (2 mL) is cooled to −78° C. and tert-butyllithium, (0.14mL, 1.7 M in pentane) is added. The mixture is warmed to 0° C. for 30min, then recooled to −78° C. and treated with titanium (IV)isopropoxide (0.30 mmol). After 30 min, aldehyde 1107 (0.30 mmol) isintroduced as a solution in tetrahydrofuran (2 mL). The resultantsolution is stirred at −78° C. for 15 min and at 0° C. for 1 h. Methyliodide (0.64 mmol) is added, and the reaction is warmed to roomtemperature for 12 h. The reaction mixture is diluted with ether (60mL), washed with aqueous sodium bisulfate (30 mL, 1.0 M), saturatedaqueous brine (30 mL), and is dried over magnesium sulfate andconcentrated in vacuo. The residue is purified by flash chromatographyto afford 1108.

E. Alcohol 1109.

To a solution of 1108 (0.050 mmol) in dichloromethane (3 mL) at 0° C. isadded water (50 mL) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.018mmol). After 1 h, the reaction mixture is diluted with ethyl acetate (50mL), washed with saturated aqueous brine (3×25 mL), dried over magnesiumsulfate and concentrated in vacuo. The residue is purified by flashchromatography to afford 1109.

F. Carbamate 1110.

To a solution of 1109 (0.010 mmol) in dichloromethane (2 mL) is addedtrichloroacetyl isocyanate (1.00 mmol). After 30 min, the reactionmixture is diluted with dichloromethane (4 mL) and neutral alumina (1 g)is added. The resultant suspension is stirred an additional 4 h. Thereaction mixture is filtered and the concentrated filtrate ischromatographed on silica gel to afford 1110.

G. Arene analog 1111.

A solution of 1110 (0.010 mmol) in 48% hydrofluoric acid-acetonitrile(1:9, 2 mL) is stirred at ambient temperature. After 12 h, saturatedaqueous sodium bicarbonate (25 mL) is added and the mixture is extractedwith ethyl acetate (3×20 mL). The combined organics are dried overmagnesium sulfate and concentrated in vacuo. The residue is purified byflash chromatography to afford 1111.

EXAMPLE 62

Synthesis of Aldehyde 67

Enone (64). To a −78° C. solution of aldehyde 27 (1.94 g, 6.13 mmolprepared from commercially available methyl (S)-(+)-3-hydroxy-2-methylpropionate generally according to Smith, et. al., J. Am. Chem. Soc.1995, 117, 12011) in CH₂Cl₂ (50 mL) was added (dropwise over 3 min) a−78° C. solution of TiCl₄ (0.68 mL, 6.18 mmol) in CH₂Cl₂ (6 mL). Theresultant solution was stirred an additional 3 min at −78° C.4-Methyl-2-trimethylsiloxy-1,3-pentadiene (1.89 g, 11.1 mmol, seePaterson, Tetrahedron Lett. 1979, 1519) was added dropwise over 2 minand the reaction mixture was further stirred at −78° C. for 2 h. Asolution comprised of pH 8 phosphate buffer (100 mL) and saturatedaqueous bicarbonate (50 mL) was added and the biphasic solution waswarmed to ambient temperature, diluted with water (100 mL), andextracted with CH₂Cl₂ (2×100 mL) The combined extracts were washed withsaturated brine (75 mL), dried (MgSO₄) and concentrated. The residualoil was diluted with CH₂Cl₂/hexanes (1:1, 30 mL), cooled to 0° C. andtreated with trichloroacetic acid (1.54 g, 9.42 mmol). After 5 h, thereaction mixture was diluted with hexanes (75 mL) and washed with water(2×50 mL), pH 8 phosphate buffer (50 mL) and saturated brine (50 mL) andwas dried (MgSO₄) and concentrated in vacuo. Flash chromatography(hexanes/CH₂Cl₂/ethyl acetate, 12:4:1) afforded 64 (1.21 g, 56%) as acolorless oil: [α]_(D) ²³ −10.6° © 0.88, CHCl₃); ¹H NMR (500 MHZ, CDCl₃)d 6.09 (m, 1 H), 4.78 (ddd, J=10.0, 6.6, 4.3 Hz, 1 H), 3.65 (t, J=2.8Hz, 1 H), 2.72 (dd, J=15.8, 4.3 Hz, 1 H), 2.66 (dd, J=15.8, 6.7 Hz, 1H), 2.62 (qd, J=7.6, 3.2 Hz, 1 H), 2.13 (d, J=1.1 Hz, 3 H), 2.07 (dqd,J=10.0, 6.8, 2.4 Hz, 1 H), 1.87 (d, J=1.2 Hz, 3 H), 1.25 (d, J=7.6 Hz, 3H), 0.97 (d, J=6.8 Hz, 3 H), 0.87 (s, 9 H), 0.05 (s, 3 H), 0.04 (s, 3H); ¹³C NMR (125 MHZ, CDCl₃) d 196.9, 173.6, 156.8, 124.1, 77.8, 74.3,47.0, 43.9, 33.6, 27.7, 25.7, 20.9, 18.0, 16.1, 13.8, −4.5, −4.7.

Alcohol (65). A solution of enone 64 (109 mg, 0.307 mmol) in toluene (8mL) was cooled to −95° C. and treated with K-Selectride (1.0 M in THF,0.35 mL). After 2 h, glacial acetic acid (0.015 mL) was added and theresultant solution was warmed to ambient temperature and treated with pH7 aqueous phosphate buffer solution (10 mL) and 30% aqueous hydrogenperoxide (0.5 mL). After 2 h, the aqueous layer was extracted withCH₂Cl₂ (4×20 mL) and the combined organics were dried (MgSO₄) andconcentrated. Flash chromatography (15% ethyl acetate/hexanes) afforded65 (70 mg, 64%) as a colorless oil: ¹H NMR (500 MHZ, CDCl₃) d 5.21(apparent dt, J=8.6, 1.3 Hz, 1 H), 4.75 (br t, J=9.1 Hz, 1 H), 4.60 (td,J=9.9, 2.3 Hz, 1 H), 3.67 (t, J=3.0 Hz, 1 H), 2.66 (qd, J=7.5, 3.4 Hz, 1H), 1.90 (dqd, 9.7, 6.8, 2.6 Hz, 1 H), 1.83 (ddd, J=14.5, 9.9, 2.4 Hz, 1H), 1.71 (d, J=1.1 Hz, 3 H), 1.70 (d, J=1.2 Hz, 3 H), 1.65 (br s, 1 H),1.60 (ddd, J=14.5, 10.1, 2.9 Hz, 1 H), 1.26 (d, J=7.6 Hz, 3 H), 0.99 (d,J=6.7 Hz, 3 H),0.89 (s, 9 H), 0.08 (s, 3 H), 0.07 (s, 3 H); ¹³C NMR (125MHZ, CDCl₃) d 174.0, 134.8, 127.7, 77.8, 74.2, 64.1, 43.7, 41.5, 34.6,25.7, 25.6, 18.2, 17.9, 16.0, 13.7, −4.6, −4.8.

Silyl Ether (66). A solution of alcohol 65 (493 mg, 1.38 mmol) andimidazole (306 mg, 4.49 mmol) in DMF (6 mL) was cooled to 0° C. andtreated with tert-butyldimethylsilyl chloride (386 mg, 2.56 mmol). Theresultant solution was stirred 12 h at ambient temperature, diluted withether (75 mL), washed with water (2×15 mL) and saturated brine (15 mL),dried over MgSO₄, and concentrated in vacuo. Flash chromatography (5%ethyl acetate/hexanes) afforded 66 (615 mg, 95%) as a colorless oil: ¹HNMR (500 MHZ, CDCl₃) d 5.11 (apparent dt, J=8.6, 1.3 Hz, 1 H), 4.71(ddd, 10.4, 8.7, 2.2 Hz, 1 H), 5.55 (td, J=10.4, 1.7 Hz, 1 H), 3.65 (t,J=2.7 Hz, 1 H), 2.63 (qd, J=7.6, 3.0 Hz, 1 H), 1.83 (dqd, 10.0, 6.8, 2.5Hz, 1 H), 1.74 (ddd, J=14.2, 10.5, 1.8 Hz, 1 H), 1.68 (d, J=1.1 Hz, 3H), 1.65 (d, J=1.2 Hz, 3 H), 1.44 (ddd, J=14.2, 10.6, 2.3 Hz, 1 H), 1.26(d, J=7.6 Hz, 3 H), 0.98 (d, J=6.7 Hz, 3 H), 0.89 (s, 9 H), 0.85 (s, 9H), 0.07 (s, 3 H), 0.06 (s, 3 H), 0.05 (s, 3 H), 0.01 (s, 3 H);

Aldehyde (67). A solution of olefin 66 (615 mg, 1.30 mmol) in CH₂Cl₂ (20mL) was cooled to −78° C. and treated with a stream of ozone and oxygenuntil the colorless solution became steel-blue in appearance. Thereaction mixture was purged with a stream of air for 10 min, followed bythe cautious addition of triphenylphosphine (375 mg, 1.42 mmol). Thecooling bath was removed and the solution was stirred at ambienttemperature for 1 h, concentrated, and chromatographed (20% ethylacetate/hexanes) to afford 67 (486 mg, 84%) as a colorless oil thatsolidified upon standing at 0° C. ¹H NMR (500 MHZ, CDCl₃) d 9.67 (br s,1 H), 4.52 (td, J=10.5, 2.1 Hz, 1 H), 4.46 (dd, J=10.5, 3.5 Hz, 1 H),3.67 (t, J=2.3 Hz, 1 H), 2.66 (qd, J=7.6, 2.6 Hz, 1 H), 1.95-1.84 (m, 3H), 1.77 (ddd, J=14.1, 10.5, 2.1 Hz, 1 H), 1.27 (d, J=7.6 Hz, 3 H), 0.99(d, J=6.7 Hz, 3 H), 0.92 (s, 9 H), 0.89 (s, 9 H), 0.13 (s, 3 H), 0.11(s, 3 H), 0.08 (s, 3 H), 0.07 (s, 3 H); ¹³C NMR (125 MHZ, CDCl₃) d203.2, 173.1, 76.0, 74.7, 73.7, 44.2, 36.2, 34.1, 25.72, 25.66, 18.1,17.9, 16.5, 14.0, −4.55, −4.63, −4.9, −5.2.

EXAMPLE 63

Synthesis of Phosphonium Salt (49) Employing Ultrahigh Pressure

Iodine (132 mg, 0.52 mmol) was added in one portion to a vigorouslystirred solution of alcohol 40 (122 mg, 0.176 mmol, prepared fromcommercially available methyl (S)-(+)-3-hydroxy-2-methyl propionategenerally according to Smith, et. al., J. Am. Chem. Soc. 1995, 117,12011), PPh₃ (172 g, 0.656 mmol) and imidazole (42 mg, 0.62 mmol) inbenzene/ether (1:2, 1.5 mL) at 0° C. The resultant solution was stirred1 h at 0° C. and 1 h at ambient temperature. The mixture was dilutedwith ether (10 mL), washed with saturated aqueous sodium metabisulfite(5 mL) and brine (10 mL), dried over MgSO₄, filtered and concentrated.Flash chromatography afforded a colorless oil (147 mg, 100 % yield).This material was combined with diisopropylethylamine (0.016 mL, 0.091mmol), triphenylphosphine (152 mg, 0.58 mmol) and benzene/toluene (7:3,1.0 mL) in a plastic syringe and subjected to a pressure of 12.8 Kbar.After 6 days, the reaction mixture was concentrated and chromatographed(10% MeCN/CHCl₃) to provide 49 [138 mg, 74% yield from 40] as a paleyellow foam: ¹H NMR (500 MHZ, CDCl₃; concentration-dependent) d7.82-7.76 (m, 15 H), 7.35 (d, J=8.8 Hz, 2 H), 6.84 (d, J=8.8 Hz, 2 H),5.35 (s, 1 H), 5.30 (d, J=10.5 Hz, 1 H), 4.07 (dd, J=11.2, 4.7 Hz, 1 H),3.77 (s, 3 H), 3.73-3.67 (m, 2 H), 3.56 (dd, J=7.0, 1.8 Hz, 1 H), 3.48(dd, J=9.8, 1.7 Hz, 1 H), 3.46 (apparent t, J=11.1 Hz, 1 H), 3.31 (ddd,J=15.6, 11.2, 11.2 Hz, 1 H), 2.49 (ddq, J=10.5, 6.4, 6.4 Hz, 1 H), 2.25(apparent t, J=12.1 Hz, 1 H), 2.10-1.92 (m, 3 H), 1.85 (dqd, J=7.1, 7.1,1.8 Hz, 1 H), 1.57-1.52 (m, 1 H), 1.56 (s, 3 H), 0.98 (d, J=7.1 Hz, 3H), 0.89 (d, J=6.6 Hz, 3 H), 0.852 (s, 9 H), 0.849 (s, 9 H), 0.72-0.71(m, 3 H), 0.71 (d, J=6.6 Hz, 3 H), 0.69 (d, J=6.9 Hz, 3 H), 0.10 (s, 3H), −0.02 (s, 3 H), −0.03 (s, 3 H), −0.07 (s, 3 H); ¹³C NMR (125 MHZ,CDCl₃) d 159.8, 135.2 (d, J_(CP)=2.6 Hz), 133.5 (d, J_(CP)=10.0 Hz),132.9, 131.4, 130.6 (d, J_(CP)=12.6 Hz), 130.3, 127.3, 118.4 (d,J_(CP)=85.5 Hz), 113.4, 101.0, 83.2, 80.1 (d, J_(CP)=14.0 Hz), 78.3,73.2, 55.3, 38.1, 37.4, 36.0, 33.7 (d, J_(CP)=4.4 Hz), 33.6, 30.7, 26.1,25.5 (d, J_(CP)=49.7 Hz), 22.9, 18.33, 18.29, 17.2, 17.1, 12.5, 12.1,10.9, −3.2, −3.6, −3.7, −4.0; high resolution mass spectrum (FAB, NBA)m/z 937.5708 [(M−I)⁺; calcd for C₅₇H₈₆O₅PSi₂: 937.5751].

EXAMPLE 64

Synthesis of Diene (76)

Phosphonium salt 49 (166 mg, 0.156 mmol), was heated to 50° C. undervacuum (0.1 torr) for 18 h, dissolved in 0.8 mL of toluene, and cooledto 0° C. The resultant solution was treated with potassiumbis(trimethylsilyl)amide (0.5 M in toluene, 0.32 mL), was stirred 20 minat 0° C. and 20 min at ambient temperature and re-chilled to −78° C.To-this reaction mixture was transferred via cannula a solution ofaldehyde 67 (58 mg, 0.13 mmol) in toluene (0.3 mL+2×0.2 mL rinse). Theresultant solution was allowed to slowly warm to −20° C. during 1 h. Asolution of pH 7 phosphate buffer was added and the biphasic solutionwas warmed to ambient temperature and extracted with CH₂Cl₂ (4×20 mL).The combined organics were dried (MgSO₄), concentrated, andchromatographed (10% ethyl acetate/hexanes) to afford 76 (83 mg, 57%) asa colorless oil that solidified upon standing: [α]_(D) ²³ +32.1° © 0.68,CHCl₃); ¹H NMR (500 MHZ, CDCl₃) d 6.97 (br d, J=8.7 Hz, 2 H), 6.87 (brd, J=8.7 Hz, 2 H), 5.34 (s, 1 H), 5.29 (dd, J=11.1, 7.8 Hz, 1 H), 5.19(t, J=10.6 Hz, 1 H), 5.07 (d, J=10.0 Hz, 1 H), 4.78 (br t, J=9.1 Hz, 1H), 4.52 (br t, J=10.0 Hz, 1 H), 4.10 (dd, J=11.1, 4.6 Hz, 1 H), 3.80(s, 3 H), 3.64 (m, 2 H), 3.54-3.46 (m, 2 H), 3.25 (t, J=5.3 Hz, 1 H),2.65-2.57 (m, 2 H), 2.51 (m, 1 H), 2.31 (t, J=12.2 Hz, 1 H), 2.06 (m, 1H), 1.96 (m, 1 H), 1.90 (dqd, J=7.1, 7.0, 1.5 Hz, 1 H), 1.78 (ddd,J=10.3, 6.6, 2.1 Hz, 1 H), 1.72 (ddd, J=14.0, 11.0, 1.5 Hz, 1 H), 1.67(br d, J=11.6 Hz, 1 H), 1.56 (m, 1 H), 1.55 (s, 3 H), 1.20 (d, J=7.6 Hz,3 H), 1.02 (d, J=7.1 Hz, 3 H), 0.92 (s, 9 H), 0.91 (s, 9 H), 0.90 (d,J=7.0 Hz, 3 H), 0.96 (d, J=6.8 Hz, 3 H), 0.95 (d, J=6.7 Hz, 3 H), 0.89(s, 9 H), 0.87 (s, 9 H), 0.75 (d, J=6.9 Hz, 3 H), 0.74 (d, J=6.7 Hz, 3H), 0.073 (s, 3 H), 0.071 (s, 3 H), 0.06 (s, 6 H), 0.05 (s, 6 H), 0.01(s, 3 H), 0.00 (s, 3 H); ¹³C NMR (125 MHZ, CDCl₃) d 173.2, 159.8, 133.6,132.4, 131.9, 131.5, 131.4, 127.3, 113.4, 101.0, 83.4, 80.4, 78.4, 76.9,74.9, 73.3, 64.7, 55.2, 44.1, 42.7, 38.0, 37.4, 35.2, 34.2, 34.0, 30.8,26.3, 26.2, 25.9, 25.7, 23.2, 18.43, 18.39, 18.1, 17.9, 17.1, 16.4,16.2, 14.0, 12.8, 12.1, 10.8, −2.9, −3.5, −3.8, −4.37, −4.41, −4.5,−4.87, −4.88. Recrystallization from hexanes afforded fine needles: mp117-119° C.

EXAMPLE 65

Synthesis of Aldehyde (77).

A solution of acetal 76 (20 mg, 0.018 mmol) in CH₂Cl₂ (2 mL) was cooledto −78° C. and diisobutylaluminum hydride (1.0 M in toluene, 0.18 mL,0.18 mmol) was added over 5 min. After an additional 10 min at −78° C.and 30 min at 0° C., the reaction was quenched with saturated aqueouspotassium sodium tartrate (0.5 mL). The mixture was then diluted withether (20 mL), washed with saturated aqueous potassium sodium tartrateand brine (10 mL each), dried over MgSO₄, filtered and concentrated.Flash chromatography (10% ethyl acetate/hexanes) provided an epimericmixture of hydroxy-lactols (14.7 mg, 74% yield) as a colorless oil. Themixture of lactols (14.7 mg, 0.0133 mmol) in CH₂Cl₂ (2 mL) was cooled to0° C. and treated with pyridinium dichromate (26 mg, 0.069 mmol). Thereaction mixture was stirred 12 h at ambient temperature, diluted withethyl acetate (10 mL), filtered (Celite) and concentrated. Flashchromatography (10% ethyl acetate/hexanes) afforded 77 (12.4 mg, 62%from 76) as a colorless oil: ¹H NMR (500 MHZ, CDCl₃) d 9.80 (d, J=2.4Hz, 1 H), 7.22 (br d, J=8.6 Hz, 2 H), 6.86 (br d, J=8.6 Hz, 2 H), 5.30(dd, J=11.1, 7.9 Hz, 1 H), 5.20 (dd, J=10.9, 10.1 Hz, 1 H), 5.11 (d,J=10.0 Hz, 1 H), 4.79 (apparent t, J=9.2 Hz, 1 H), 4.52 (br t, J=9.6 Hz,1 H), 4.47 (s, 2 H), 3.80 (s, 3 H), 3.62 (t, J=2.5 Hz, 1 H), 3.59 (m, 2H), 3.26 (t, J=5.3 Hz, 1 H), 2.75 (m, 1 H), 2.62 (m, 2 H), 2.50 (m, 1H), 2.24 (t, J=12.4 Hz, 1 H), 1.99-1.88 (m, 2 H), 1.83-1.65 (m, 3 H),1.59 (s, 3 H), 1.58 (m, 1 H), 1.21 (d, J=7.6 Hz, 3 H), 1.13 (d, J=7.0Hz, 3 H), 1.04 (d, J=7.0 Hz, 3 H), 0.96 (d, J=6.8 Hz, 3 H), 0.95 (d,J=6.9 Hz, 3 H), 0.94 (s, 9H), 0.91 (s, 9 H), 0.89 (d, J=6.9 Hz, 3 H),0.88 (s, 9 H), 0.87 (s, 9 H), 0.75 (d, J=6.8 Hz, 3 H), 0.09 (s, 3 H),0.08 (s, 3 H), 0.07 (s, 3 H), 0.06 (s, 6 H), 0.05 (s, 6 H), 0.01 (s, 3H); ¹³C NMR (125 MHZ, CDCl₃) d 204.5, 173.2, 159.3, 133.5, 132.5, 132.3,130.8, 130.3, 129.1, 113.8, 82.6, 80.4, 76.9, 74.9, 74.4, 64.6, 55.3,49.5, 44.1, 42.7, 40.3, 37.4, 36.8, 35.2, 35.0, 34.2, 26.3, 26.2, 25.9,25.7, 23.1, 18.5, 18.4, 18.1, 17.9, 17.1, 16.4, 16.2, 14.1, 13.4, 12.2,11.4, −3.0, −3.3, −3.4, −4.3, −4.4, −4.5, −4.9.

EXAMPLE 66

Synthesis of Tetraene (58)

Method A. A solution of allyldiphenylphosphine (0.0035 mL, 0.0162 mmol)in anhydrous THF was cooled to −78° C. and t-BuLi (1.7 M in pentane,0.010 mL, 0.017 mmol) was added. The mixture was stirred at 0° C. for 30min, recooled to −78° C. and treated Ti(OiPr)₄ (0.005 mL, 0.017 mmol).After 30 min, a cold (−78° C.) solution of the aldehyde 77 (3.5 mg,0.0032 mmol) in THF (0.25 mL +0.25 mL rinse) was introduced via cannula,and the mixture was stirred 10 min further at −78° C. and at 0° C. for30 min. Methyl Iodide (0.0025 mL, 0.04 mmol) was then added, and thereaction was warmed to room temperature and stirred overnight. Thereaction mixture was diluted with ether (10 mL), washed with 1.0 Maqueous NaHSO₄ and brine (5 mL each), dried over MgSO₄, filtered andconcentrated in vacuo. Flash chromatography (2% ethyl acetate/hexane)gave a 1.2:1 mixture of Z/E isomers (2.1 mg, 58%) as an oil. Pipetteflash chromatography on 10% silver nitrate-silica gel (5% ether/hexanes)furnished the Z-olefin 58 as a colorless oil: ¹H NMR (500 MHZ, CDCl₃) d7.25 (d, J=8.2 Hz, 2 H), 6.84 (d, J=8.7 Hz, 2 H), 6.57 (dddd, J=16.8,11.0, 11.0, 0.7 Hz, 1 H), 6.00 (apparent t, J=11.1 Hz, 1 H), 5.55(apparent t, J=10.5 Hz, 1 H), 5.26 (dd, J=11.2, 7.8 Hz, 1 H), 5.20-5.16(m, 2 H), 5.09 (d, J=10.1 Hz, 1 H), 5.05 (d, J=2.2 Hz, 1 H), 5.03 (d,J=10.0 Hz, 1 H), 4.67 (apparent t, J=9.1 Hz, 1 H), 4.49 (AB_(q),J_(AB)=10.6 Hz, Δγ_(AB)=41.3 Hz, 2 H), 3.78 (s, 3 H), 3.68 (apparent t,J=10.2 Hz, 1 H), 3.52 (apparent t, J=2.6 Hz, 1 H), 3.43 (dd, J=4.8, 3.9Hz, 1 H), 3.24-3.21 (m, 2 H), 3.01-2.94 (m, 1 H), 2.67 (dq, J=12.8, 7.4Hz, 1 H), 2.61 (dq, J=12.8, 7.5 Hz, 1 H), 2.71-2.57 (m, 1 H), 2.46-2.39(m, 1 H), 2.00 (apparent t, J=12.4 Hz, 1 H), 1.83-1.73 (m, 3 H), 1.64(br d, J=14.0 Hz, 1 H), 1.62-1.52 (m, 2 H), 1.55 (d, J=0.5 Hz, 3 H),1.36 (ddd, J=13.7, 10.8, 1.5 Hz, 1 H), 1.26 (d, J=7.4 Hz, 3 H), 1.25 (d,J=7.4 Hz, 3 H), 1.08 (d, J=6.8 Hz, 3 H), 0.98 (d, J=6.8 Hz, 3 H), 0.94(d, J=7.1 Hz, 3 H), 0.93 (s, 9 H), 0.90 (s, 9 H), 0.89 (s, 9 H),0.89-0.86 (m, 3 H), 0.86 (s, 9 H), 0.73 (d, J=6.8 Hz, 3 H), 0.70 (d,J=6.7 Hz, 3 H), 0.08 (s, 6 H), 0.05 (s, 3 H), 0.02 (s, 3 H), 0.013 (s, 3H), 0.010 (s, 6 H), −0.02 (s, 3 H); ¹³C NMR (125 MHZ, CDCl₃) d 159.1,134.5, 134.3, 132.2, 131.9, 131.8, 131.2, 129.13, 129.07, 117.6, 113.7,84.6, 80.9, 80.5, 76.5, 75.0, 74.2, 65.5, 55.3, 42.5, 41.9, 40.2, 37.2,36.1, 35.4, 35.3, 34.5, 29.7, 26.3, 26.0, 25.9, 25.1, 23.1, 18.7, 18.6,18.5, 18.14, 18.09, 17.0, 16.8, 15.6, 14.8, 14.4, 11.6, 10.6, −2.8,−3.2, −3.3, −3.6, −4.2, −4.5, −4.90, −4.93; high resolution massspectrum (FAB, NBA) m/z 1195.8001 [(M+Na)⁺; calcd for C₆₆H₁₂₄O₇SSi₄Na:1195.8042].

Method B. A vigorously stirred suspension of chromium(III) chloride (7.8mg, 0.048 mmol) in anhydrous THF (0.6 mL) was cooled to 0° C. andtreated with lithium aluminum hydride (1.0 M in ether, 0.022 mL, 0.022mmol). The resultant solution was stirred 20 min at room temperature andre-cooled to 0° C. Aldehyde 77 (3.9 mg, 0.035 mmol) was added in THF(0.4 mL). After 10 min, a mixture of 3-bromo-1-trimethylsilyl-1-propeneand 3-bromo-3-trimethlsilyl-1-propene (3:1, 0.002 mL, 0.01 mmol, see,Hodgson, et. al., Tetrahedron Lett. 1992, 33, 4761) was added. Thereaction mixture was stirred at ambient temperature for 12 h and thendiluted with hexanes-ethyl acetate (9:1), washed with water, saturatedaqueous sodium bicarbonate and brine, dried over MgSO₄ and concentrated.Flash chromatography afforded a 2.8:1 mixture of hydroxy silanes (3.8mg, 89%). The mixture was dissolved in THF (0.6 mL), cooled to 0° C. andtreated with potassium bis(trimethylsilyl)amide (0.5 M in toluene, 0.068mL, 0.34 mmol). After 15 min, trichloroacetic acid (5 mg, 0.03 mmol) wasadded and the reaction mixture was diluted with hexanes and washed withwater and brine. The combined aqueous washings were further extractedwith hexanes. The combine organics were dried over MgSO₄ andconcentrated in vacuo. Flash Chromatography afforded (2.6 mg, 65% yieldfor 2 steps) of tetraene 58 as a colorless oil.

Method C. Phosphonium salt 75 (120 mg, 0.11 mmol) was heated to 50° C.under vacuum (0.1 torr) for 18 h and dissolved in 0.4 mL of anhydroustoluene. The resultant solution was cooled to 0° C. and was treated withpotassium bis(trimethylsilyl)amide (0.5 M in toluene, 0.23 mL, 0.115mmol). The resultant solution was stirred 20 min at 0° C. and 20 min atambient temperature before being chilled to −78° C. Aldehyde 67(46 mg,0.10 mmol) was added in toluene (0.4 mL) and the reaction mixture wasallowed to warm to 0° C. during 2.5 h. The reaction was partitionedbetween hexanes (10 mL) and pH 7 phosphate buffer solution(10 mL). Theaqueous layer was extracted with CH₂Cl₂ (4×15 mL) and the combinedorganics were dried over MgSO₄ and concentrated. Flash chromatographyafforded tetraene 58 (49 mg, 42% yield).

EXAMPLE 67

Synthesis of Alcohol (71).

A solution of (+)-39 (106 mg, 0.13 mmol, prepared from commerciallyavailable methyl (S)-(+)-3-hydroxy-2-methyl propionate generally asdescribed by Smith, et. al., J. Am. Chem. Soc. 1995, 117, 12011)) inCH₂Cl₂ was cooled to 0° C. and treated with neat diisobutylaluminumhydride (0.15 mL, 0.84 mmol). After 1 h, a solution of saturated aqueouspotassium sodium tartrate (10 mL) was added (dropwise until cessation ofhydrogen evolution) and the resultant biphasic mixture was stirred 4 hat ambient temperature. The aqueous layer was extracted with CH₂Cl₂(3×10 mL) and the combined organics were dried over MgSO₄ andconcentrated in vacuo. Flash chromatography (15% ethyl acetate/hexanes)afforded alcohol 71 (88 mg, 83%) as a colorless oil: ¹H NMR (500 MHZ,CDCl₃) d 7.26-7.20 (m, 4 H), 6.87-6.82 (m, 4 H), 5.03 (br d, J=10.2 Hz,1 H), 4.50 (AB_(q), J=10.5 Hz, Dv=12.1 Hz, 2 H), 4.37 (AB_(q), J=11.6Hz, Dv=14.2 Hz, 2 H), 3.78 (s, 3 H), 3.77 (s, 3 H), 3.74 (m, 1 H), 3.57(quintet, J=10.5 Hz, 1 H), 3.51 (dd, J=5.1, 3.7 Hz, 1 H), 3.47 (dd,J=9.1, 4.9 Hz, 1 H), 3.38 (dd, J=6.0, 4.6 Hz, 1 H), 3.35 (t, J=5.5 Hz, 1H), 3.20 (t, dd, J=8.9, 8.6 Hz, 1 H), 2.68 (br t, J=5.5 Hz, 1 H), 2.51(m, 1 H), 2.22 (br t, J=12.4 Hz, 1 H), 2.00-1.84 (m, 4 H), 1.74 (br d,J=12.5 Hz, 1 H), 1.58 (d, J=0.9 Hz, 3 H), 1.04 (d, J=7.3 Hz, 3 H), 1.02(d, J=7.2 Hz, 3 H), 0.93 (d, J=7.0 Hz, 3 H), 0.92 (s, 9 H), 0.88 (d,J=6.9 Hz, 3 H), 0.87 (s, 9 H), 0.07 (s, 3 H), 0.06 (s, 3 H), 0.02 (s, 3H), 0.1 (s, 3 H); ¹³C NMR (125 MHZ, CDCl₃) d 159.4, 159.0, 131.64,131.60, 131.0, 130.4, 129.3, 129.0, 113.9, 113.7, 86.2, 78.4, 77.5,75.2, 72.7, 72.6, 65.4, 55.3, 39.9, 38.7, 37.5, 36.7, 35.7, 35.2, 26.2,26.1, 23.1, 18.5, 18.4, 17.0, 15.7, 14.6, 13.7, 11.4, −3.3, −3.4, −3.9.

EXAMPLE 68

Synthesis of Aldehyde (72).

A solution of alcohol 71(88 mg, 0.108 mmol) and triethylamine (0.075 mL,0.54 mmol) in CH₂Cl₂ (2 mL) and dimethylsulfoxide (1 mL) was treatedwith sulfur trioxide-pyridine (55 mg, 0.34 mmol). After 90 min, themixture was diluted with ether (30 mL), washed with water (10 mL),aqueous NaHSO₄ (0.1 M, 10 mL) and brine (10 mL), dried over MgSO₄,filtered and concentrated. Flash chromatography (5% ethylacetate/hexanes) afforded 72 (84 mg, 96% yield) as a colorless oil: ¹HNMR (500 MHZ, CDCl₃) d 9.79 (d, J=2.4 Hz, 1 H), 7.24-7.18 (m, 4 H),6.87-6.82 (m, 4 H), 5.03 (br d, J=10.2 Hz, 1 H), 4.46 (AB_(q), J=10.8Hz, Dv=7.1 Hz, 2 H), 4.37 (AB_(q), J=11.6 Hz, Dv=14.0 Hz, 2 H), 3.78 (s,3 H), 3.77 (s, 3 H), 3.57 (m, 2 H), 3.47 (dd, J=9.1, 5.0 Hz, 1 H), 3.39(dd, J=5.9, 4.7 Hz, 1 H), 3.21 (t, J=8.7 Hz, 1 H), 2.73 (m, 1 H), 2.51(m, 1 H), 2.25 (t, J=12.4 Hz, 1 H), 1.99-1.86 (m, 3 H), 1.70 (br d,J=12.4 Hz, 1 H), 1.58 (s, 3 H), 1.12 (d, J=7.0 Hz, 3 H), 1.03 (d, J=7.0Hz, 3 H), 0.93 (d, J=7.0 Hz, 3 H), 0.92 (s, 9 H), 0.88 (d, J=6.9 Hz, 3H), 0.87 (s, 9 H), 0.74 (d, J=6.8 Hz, 3 H), 0.07 (s, 3 H), 0.06 (s, 3H), 0.02 (s, 3 H), 0.01 (s, 3 H); ¹³C NMR (125 MHZ, CDCl₃) d 204.5,159.3, 159.0, 131.7, 131.5, 131.0, 130.3, 129.1, 129.0, 113.8, 113.7,82.6, 78.4, 77.2, 74.4, 72.7, 72.5, 55.25, 55.24, 49.5, 40.3, 38.7,36.7, 35.7, 35.0, 26.2, 26.1, 23.1, 18.5, 18.4, 17.0, 14.6, 13.4, 12.2,11.4, −3.3, −3.4, −3.89, −3.91.

EXAMPLE 69

Synthesis of Triene (73).

A solution lithium aluminum hydride (1.0 M in ether, 0.022 mL, 0.022mmol).was added dropwise to a vigorously stirred suspension ofchromium(III) chloride (40 mg, 0.25 mmol) in anhydrous THF (2 mL) at 0°C. The resultant solution was stirred 45 min at room temperature andre-cooled to 0° C. Aldehyde 72 (50 mg, 0.061 mmol) was added in THF (3mL) via cannula. After 10 min, a mixture of3-bromo-1-trimethylsilyl-1-propene and 3-bromo-3-trimethlsilyl-1-propene(3:1, 0.025 mL, 0.13 mmol) was added. The reaction mixture was furtherstirred 30 min at 0° C. and at ambient temperature for 12 h. Methanol (1mL) and aqueous potassium hydroxide solution (6 M, 2 mL) were added andthe resultant solution was stirred 1 h at ambient temperature. Theaqueous layer was extracted with hexanes (3×15 mL). The combinedorganics were washed with brine, dried over MgSO₄ and concentrated.Flash chromatography provided triene 73 (47 mg, 92%) as a singlegeometric isomer: ¹H NMR (500 MHZ, CDCl₃) d 7.27-7.20 (m, 4 H),6.87-6.82 (m, 4 H), 6.57 (dt, J=16.8, 10.4 Hz, 1 H), 6.00 (t, J=11.0 Hz,1 H), 5.55 (t, J=10.5 Hz, 1 H), 5.18 (dd, J=16.8, 1.6 Hz, 1 H), 5.09 (d,J=10.1 Hz, 1 H), 4.96 (d, J=10.2 Hz, 1 H), 4.50 (AB_(q), J=10.6 Hz,Dv=43.6 Hz, 2 H), 4.36 (AB_(q), J=11.6 Hz, Dv=16.9 Hz, 2 H), 3.78 (s, 3H), 3.77 (s, 3 H), 3.44 (m, 2 H), 3.36 (dd, J=6.4, 4.4 Hz, 1 H), 3.24(dd, J=7.4, 3.7 Hz, 1 H), 3.19 (t, J=8.8 Hz, 1 H), 2.98 (m, 1 H), 2.44(m, 1 H), 2.03 (t, J=12.4 Hz, 1 H), 1.95 (m, 1 H), 1.84-1.72 (m, 2 H),1.65 (br d, J=11.4 Hz, 1 H), 1.52 (s, 3 H), 1.09 (d, J=6.8 Hz, 3 H),0.99 (d, J=6.9 Hz, 3 H), 0.93 (s, 9 H), 0.91 (d, J=7.0 Hz, 3 H), 0.87(s, 9 H), 0.85 (d, J=6.6 Hz, 3 H), 0.70 (d, J=6.7 Hz, 3 H), 0.09 (s, 3H), 0.08 (s, 3 H), 0.01 (s, 6 H); ¹³C NMR (125 MHZ, CDCl₃) d 159.1,159.0, 134.5, 132.2, 131.8, 131.2, 131.1, 129.1, 129.0, 117.6, 113.7,84.6, 78.4, 77.2, 75.0, 72.7, 72.5, 55.3, 40.1, 38.9, 36.1, 35.5, 35.4,26.3, 26.1, 23.0, 18.7, 18.6, 18.4, 17.2, 14.7, 14.4, 10.6, −3.2, −3.3,−3.89, −3.92.

EXAMPLE 70

Synthesis of Alcohol (74).

Method A: Bis-ether 73 is dissolved in a mixture of CH₂Cl₂ and water(19:1) and cooled to 0° C. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (1eq) is added and the resultant solution is stirred 2 h at 0° C. Thereaction mixture is diluted with hexanes and washed with aqueous sodiumhydroxide solution, dried over MgSO₄ and concentrated. Flashchromatography affords 74.

Method B: A solution of 73 and ethanethiol in CH₂Cl₂ is cooled to −78°C. and treated with a Lewis acid (e.g. magnesium bromide,borontrifluoride etherate, tin(IV) chloride, titanium(IV) chloride,etc.). The resultant solution is allowed to slowly warm until reactionensues. The reaction is then quenched with aqueous sodium hydroxidesolution, washed with water and brine, dried over MgSO₄, concentratedand chromatographed to afford 74: ¹H NMR (500 MHZ, CDCl₃) d 7.27 (br d,J=8.6 Hz, 2 H), 6.87 (br d, J=8.6 Hz, 2 H), 6.60 (dt, J=16.8, 10.5 Hz, 1H), 6.04 (t, J=11.0 Hz, 1 H), 5.57 (t, J=10.5 Hz, 1 H), 5.55 (dd,J=16.8, 1.8 Hz, 1 H), 5.12 (d, J=10.3 Hz, 1 H), 4.97 (d, J=10.2 Hz, 1H), 4.51 (AB_(quartet), J=10.6 Hz, Dv=47.6 Hz, 2 H), 3.80 (s, 3 H), 3.66(dt, J=10.9, 4.3 Hz, 1 H), 3.50 (m, 1 H), 3.44 (dd, J=4.8, 4.0 Hz, 1 H),3.39 (dd, 6.9, 3.8 Hz, 1 H), 3.25 (dd, J=7.4, 3.7 Hz, 1 H), 3.00 (m, 1H), 2.54 (m, 1 H), 2.31 (br t, J=5.5 Hz, OH), 2.05 (t, J=12.4 Hz, 1 H),1.85-1.73 (m, 3 H), 1.67 (br d, J=13.4 Hz, 1 H), 1,56 (s, 3 H), 1.11 (d,J=6.8 Hz, 3 H), 1.00 (d, J=7.0 Hz, 3 H), 0.99 (d, J=7.0 Hz, 3 H), 0.95(s, 9 H), 0.92 (s, 9 H), 0.91 (d, =6.6 Hz, 3 H), 0.72 (d, J=6.7 Hz, 3H), 0.10 (s, 9 H), 0.07 (s, 3 H).

EXAMPLE 71

Synthesis of Phosphonium Salt (75).

Iodine (127 mg, 0.50 mmol) was added in one portion to a vigorouslystirred solution of alcohol 74 (120 mg, 0.167 mmol), triphenylphosphine(156 mg, 0.595 mmol), and imidazole (40 mg, 0.59 mmol) in benzene/ether(1:1) at −10° C. The resultant solution was stirred 30 min at −10° C.and 30 min at ambient temperature, was diluted with 30 mL hexanes andwas washed with water (2×10 mL), saturated aqueous sodium metabisulfite(10 mL), saturated aqueous sodium bicarbonate (10 mL) and saturatedbrine (10 mL), dried over MgSO₄ and concentrated. Flash chromatography(2% ether/hexanes) provided a colorless oil. The oil was combined withdiisopropylethylamine (0.015 mL, 0.086 mmol), triphenylphosphine (199mg, 0.758 mmol), and benzene/toluene (7:3, 1.0 mL) in a plastic syringeand was subjected to a pressure of 12.8 Kbar. After 16 days, thereaction mixture was concentrated and chromatographed (10%acetonitrile/chloroform) to afford phosphonium salt 75 (126 mg, 76% fortwo steps) as a pale yellow film: ¹H NMR (500 MHZ, CDCl₃) d 8.84-7.65(m, 15 H), 7.27 (br d, J=8.6 Hz, 2 H), 6.87 (br d, J=8.6 Hz, 2 H), 6.54(dt, J=16.8, 10.5 Hz, 1 H), 5,89 (t, J=11.0 Hz, 1 H), 5.51 (t, J=10.5Hz, 1 H), 5.30 (d, J=10.5 Hz, 1 H), 5.21 (d, J=16.8, 1 H), 5.08 (d,J=10.2 Hz, 1 H), 4.51 (AB_(q), J=10.4 Hz, Dv=55.6 Hz, 2 H), 3.78 (s, 3H), 3.76-3.68 (m, 2 H), 3.42 (dd, J=5.4, 3.1 Hz, 1 H), 3.25-3.17 (m, 2H), 2.97 (m, 1 H), 2.41 (m, 1 H), 2.06 (m, 1 H), 1.95 (t, J=12.3 Hz, 1H), 1.77-1.72 (m, 2 H), 1.58 (br d, J=11.9 Hz, 1 H), 1.53 (s, 3 H), 1.10(d, J=6.8 Hz, 3 H), 0.96 (d, J=6.8 Hz, 3 H), 0.91 (s, 9 H), 0.89 (d,J=7.0 Hz, 3 H), 0.86 (s, 9 H), 0. 69 (d, J=6.9 Hz, 3 H), 0.66 (d, J=6.7Hz, 3 H), 0.09 (s, 3 H), 0.08 (s, 3 H), 0.04 (s, 3 H), −0.05 (s, 3 H).

EXAMPLE 72

Synthesis of Alcohol (+)-59.

At 0° C., a solution of PMB ether (+)-58 (4.0 mg, 3.55 mmol) in CH₂Cl₂(0.5 mL) was treated with H₂O (50 mL) and DDQ (3.0 mg, 13.2 mmol). Themixture was stirred for 1 h and then diluted with ethyl acetate (30 mL),washed with brine (3×30 mL), dried over MgSO₄, filtered andconcentrated. Pipette flash chromatography (2% ethyl acetate/hexanes)provided 59 (3.4 mg, 95% yield) as a colorless oil: ¹H NMR (500 MHZ,CDCl₃) d 6.61 (ddd, J=16.8, 10.9, 10.9 Hz, 1 H), 6.13 (apparent t,J=11.0 Hz, 1 H), 5.32 (apparent t, J=10.5 Hz, 1 H), 5.28 (dd, J=11.1,7.9 Hz, 1 H), 5.24-5.21 (m, 1 H), 5.19 (apparent t, J=10.3 Hz, 1 H),5.14 (d, J=10.2 Hz, 1 H), 5.06 (d, J=10.0 Hz, 1 H), 4.76 (apparent t,J=9.3 Hz, 1 H), 4.50 (apparent t, J=9.9 Hz, 1 H), 3.62 (apparent t,J=2.4 Hz, 1 H), 3.60 (dd, J=5.5, 3.4 Hz, 1 H), 3.32 (br d, J=5.3 Hz, 1H), 3.24 (apparent t, J=5.1 Hz, 1 H), 2.79 (ddq, J=9.9, 6.7, 6.7 Hz, 1H), 2.60 (qd, J=7.6, 2.7 Hz, 1 H), 2.63-2.57 (m, 1 H), 2.50-2.45 (m, 1H), 2.16 (apparent t, J=12.3 Hz, 1 H), 1.90-1.77 (m, 3 H), 1.75-1.69 (m,2 H), 1.57 (s, 3 H), 1.60-1.50 (m, 1 H), 1.20 (d, J=7.6 Hz, 3 H), 0.96(d, J=6.8 Hz, 3 H), 0.95 (d, J=6.6 Hz, 3 H), 0.95-0.93 (m, 6 H), 0.91(s, 9 H), 0.89 (s, 9 H), 0.89-0.84 (m, 3 H), 0.87 (s, 9 H), 0.85 (s, 9H), 0.73 (d, J=6.8 Hz, 3 H), 0.07 (apparent s, 6 H), 0.052 (s, 3 H),0.051 (s, 3 H), 0.04 (apparent s, 6 H), 0.03 (s, 3 H), −0.01 (s, 3 H);¹³C NMR (125 MHZ, CDCl₃) d 173.3, 134.7, 133.5, 132.5, 132.1, 132.0,131.5, 131.0, 118.4, 80.5, 78.8, 76.4, 74.9, 64.7, 44.1, 42.7, 38.0,37.4, 36.3, 36.1, 35.2, 35.1, 34.2, 26.3, 26.2, 25.9, 25.7, 23.2, 18.5,18.1, 18.0, 17.3, 17.2, 16.4, 16.1, 14.1, 13.7, 9.4, −3.0, −3.3, −3.6,−4.34, −4.36, −4.5, −4.8; high resolution mass spectrum (FAB, NBA) m/z1029.7273 [(M+Na)⁺; calcd for C₅₆H₁₁₀O₇Si₄Na: 1029.7226].

EXAMPLE 73

Synthesis of Carbamate (+)-60

A solution of alcohol 59 (2.2 mg, 2.19 mmol) in CH₂Cl₂ (0.5 mL) wastreated with trichloroacetyl isocyanate (20 mL, 0.17 mmol) at roomtemperature for 30 min. CH₂Cl₂ (2.0 mL) and neutral alumina (500 mg)were then added and the mixture was stirred at room temperature for 2 h,filtered through a short plug of silica, and concentrated. Pipette flashchromatography (10% ethyl acetate/hexane) furnished 60 (1.9 mg, 83%yield) as a colorless oil: IR (film, NaCl) 3510 (m), 3360 (m, br), 3180(m), 2960 (s), 2930 (s), 2880 (s), 2855 (s), 1730 (s, br), 1596 (m),1460 (s), 1385 (s), 1362 (s), 1325 (m), 1255 (s), 1220 (m), 1100 (s),1043 (s), 983 (m), 937 (m), 904 (m), 832 (s) 770 (s), 663 (m) cm⁻¹; ¹HNMR (500 MHZ, CDCl₃) d 6.58 (dddd, J=16.8, 10.6, 10.6, 0.7 Hz, 1 H),6.01 (apparent t, J=11.0 Hz, 1 H), 5.36 (apparent t, J=10.4 Hz, 1 H),5.27 (dd, J=11.1, 7.9 Hz, 1 H), 5.22-5.16 (m, 2 H), 5.12 (d, J=10.1 Hz,1 H), 5.03 (d, J=10.0 Hz, 1 H), 4.76 (apparent t, J=9.2 Hz, 1 H), 4.71(apparent t, J=6.1 Hz, 1 H), 4.50 (ddd, J=10.5, 10.5, 1.3 Hz, 1 H), 4.44(br s, 2 H), 3.62 (apparent t, J=2.4 Hz, 1 H), 3.42 (apparent t, J=4.5Hz, 1 H), 3.22 (apparent t, J=5.3 Hz, 1 H), 2.98 (ddq, J=10.1, 6.6, 6.6Hz, 1 H), 2.60 (qd, J=7.6, 2.7 Hz, 1 H), 2.63-2.55 (m, 1 H), 2.48-2.41(m, 1 H), 2.09 (apparent t, J=12.4 Hz, 1 H), 1.93-1.88 (m, 1 H),1.87-1.77 (m, 2 H), 1.71 (ddd, J=14.1, 10.8, 1.6 Hz, 1 H), 1.67 (br d,J=13.7 Hz, 1 H), 1.56 (apparent s, 3 H), 1.55-1.50 (m, 1 H), 1.21 (d,J=7.6 Hz, 3 H), 0.98 (d, J=6.8 Hz, 3 H), 0.95 (d, J=7.0 Hz, 3 H), 0.94(d, J=7.5 Hz, 3 H), 0.918 (d, J=6.8 Hz, 3 H), 0.915 (s, 9 H), 0.89 (s, 9H), 0.86 (s, 9 H), 0.853 (d, J=6.4 Hz, 3 H), 0.847 (s, 9 H), 0.70 (d,J=6.8 Hz, 3 H), 0.09 (s, 3 H), 0.07 (s, 3 H), 0.053 (s, 3 H), 0.051 (s,3 H), 0.040 (s, 3 H), 0.037 (s, 3 H), 0.03 (s, 3 H), −0.02 (s, 3 H); ¹³CNMR (125 MHZ, CDCl₃) d 173.3, 156.9, 133.6, 133.5, 132.4, 132.1, 131.9,131.4, 129.8, 118.0, 80.5, 78.9, 74.9, 64.6, 44.2, 42.7, 37.8, 37.4,36.0, 35.3, 35.2, 34.5, 34.2, 26.3, 26.2, 25.9, 25.7, 23.0, 18.5, 18.4,18.1, 18.0, 17.5, 17.1, 16.44, 16.38, 14.1, 13.7, 10.1, −3.0, −3.4,−3.6, −4.4, −4.5, −4.8; high resolution mass spectrum (FAB, NBA) m/z1072.7264 [(M+Na)⁺; calcd for C₅₇H₁₁₁NO₈Si₄Na: 1072.7283].

EXAMPLE 74

Synthesis of (+)-Discodermolide.

Tetrasilyl derivative (+)-60 (5.8 mg, 5.5 mmol) was dissolved in 48%HF—CH₃CN (1:9, 1.0 mL) at room temperature. After 12 h, the reactionmixture was quenched with saturated aqueous NaHCO₃ (5 mL) and extractedwith ethyl acetate (3×10 mL). The combined extracts were washed withbrine (5 mL), dried over MgSO₄, filtered and concentrated. Pipette flashchromatography (gradient elution; 1:30→1:6 MeOH/CHCl₃) gave (+)-1 (2.0mg, 60% yield) as a white amorphous solid: [α]_(D) ²³ +15° © 0.033,MeOH); IR (CHCl₃) 3690 (w), 3620 (w), 3540 (w), 3430 (w), 3020 (s), 2975(m), 2935 (m), 1740 (m), 1590 (w), 1540 (w), 1520 (w), 1467 (w), 1430(w), 1385 (m), 1330 (w), 1233 (s), 1210 (S), 1100 (w), 1045 (m), 1033(m), 975 (w), 930 (m) 910 (w), 793 (m), 777 (m), 765 (m), 750 (m), 705(m), 687 (m) 670 (m), 660 (m), 625 (w) cm⁻¹; ¹H NMR (500 MHZ, CDCl₃) d6.60 (dddd, J=16.8, 8.4, 8.4, 0.8 Hz, 1 H), 6.02 (apparent t, J=11.1 Hz,1 H), 5.51 (dd, J=11.2, 7.9 Hz, 1 H), 5.42 (ddd, J=10.6, 10.6, 0.6 Hz, 1H), 5.34 (apparent t, J=10.4 Hz, 1 H), 5.20 (dd, J=16.9, 1.9 Hz, 1 H),5.16 (d, J=10.0 Hz, 1 H), 5.11 (d, J=10.1 Hz, 1 H), 4.77-4.69 (m, 1 H),4.70 (dd, J=7.3, 4.2 Hz, 1 H), 4.60 (ddd, J=10.0, 10.0, 2.4 Hz, 1 H),4.56 (br s, 2 H), 3.73 (m, 1 H), 3.28 (m, 1 H), 3.18 (dd, J=6.8, 4.8 Hz,1 H), 2.98 (ddq, J=10.1, 6.9, 6.9 Hz, 1 H), 2.78 (ddq, J=9.8, 6.8, 6.8Hz, 1 H), 2.66 (qd, J=7.3, 4.6 Hz, 1 H), 2.60-2.55 (m, 1 H), 2.10-1.80(m, 10 H), 1.69 (ddd, J=14.4, 10.3, 3.1 Hz, 1 H), 1.64 (d, J=1.3 Hz, 3H), 1.30 (d, J=7.4 Hz, 3 H), 1.06 (d, J=6.9 Hz, 3 H), 1.00 (d, J=6.8 Hz,3 H), 0.99 (d, J=6.7 Hz, 3 H), 0.97 (d, J=6.8 Hz, 3 H), 0.94 (d, J=6.8Hz, 3 H), 0.82 (d, J=6.3 Hz, 3 H); ¹³C NMR (125 MHZ, CDCl₃) d 173.6,157.0, 134.4, 133.7, 133.4, 132.9, 132.2, 129.9, 129.8, 117.9, 79.1,78.9, 77.1, 75.7, 73.2, 64.4, 43.1, 41.0, 37.4, 36.1, 36.0, 35.8, 35.3,34.8, 33.1, 23.3, 18.4, 17.4, 15.6, 15.5, 13.7, 12.5, 9.0; highresolution mass spectrum (FAB, NBA) m/z 616.3840 [(M+Na)⁺; calcd forC₃₃H₅₅NO₈Na: 616.3826].

EXAMPLE 75

I. General Procedure for Synthesis of Siloxy Aldehydes (85).

A. A solution of organolithium (M=Li, FIG. 41)) of type 80-83 (20 mmol)in ether (40 mL) is added slowly to a 0° C. solution of benzyl(S)-(+)-glycidyl ether (9 mmol) in ether (20 mL). The reaction isallowed to warm to room temperature. After 18-24 h, the reaction mixtureis quenched by the addition of tert-butyldimethylsilyl triflate (10mmol) and poured into saturated aqueous sodium bicarbonate (100 mL). Theaqueous layer is separated and extracted with ether (2×50 mL). Thecombined organics are washed with saturated aqueous brine (50 mL), driedover magnesium sulfate and concentrated in vacuo. The residue ispurified by flash chromatography to afford an alpha-siloxy benzyl ether.

B. To a solution of the above benzyl ether (6 mmol) in ethylacetate-ethanol (8:1, 90 mL) is added palladium on carbon (10% wet, 500mg). The mixture is stirred under hydrogen atmosphere for 3-6 h, thenfiltered and concentrated in vacuo. The residue is purified by flashchromatography to afford an alcohol.

C. Aldehyde 85.

Oxalyl chloride (1.5 mmol) is added dropwise to a −78° C. solution ofdimethyl sulfoxide (3 mmol) in dichloromethane (4 mL). After 15 min, a−78° C. solution of the alcohol prepared in part B (1 mmol) indichloromethane (2 mL) is added via canula. After an additional 15 min,diisopropylethylamine (4.5 mmol) is added and the reaction is graduallywarmed to room temperature over 1 h and quenched with aqueous sodiumbisulfate. The mixture is diluted with ether (50 mL) and is washed withwater (2×30 mL), saturated aqueous brine (2×30 mL), is dried overmagnesium sulfate and concentrated in vacuo. The residue is purified byflash chromatography to afford 85.

II. General Procedure for the Conversion of (85) to Tetraene (86).

D. Phosphonium salt 75 (0.2 mmol) is dissolved in anhydroustetrahydrofuran (2 mL) and chilled to 0° C. A solution of potassiumbis(trimethylsilyl)amide (0.2 mmol, 0.5 M in tetrahydrofuran) is addedand the reaction mixture is stirred 30 min at 0° C. After cooling to−78° C., a solution of aldehyde 85 (0.1 mmol) in tetrahydrofuran (2 mL)is added and the mixture is stirred 10 min at −78° C. and 2 h at roomtemperature. Saturated aqueous ammonium chloride (2 mL) is added and theresultant mixture is extracted with ether (3×20 mL). The ethereal layeris washed with water (2×25 mL) and saturated aqueous brine (25 mL),dried over magnesium sulfate and concentrated in vacuo. The residue ispurified by flash chromatography to afford a tetraene.

E. To a solution of the tetraene prepared in part D (0.050 mmol) indichloromethane (3 mL) at 0° C. is added water (0.050 mL) and2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.018 mmol). After 1 h, thereaction mixture is diluted with ethyl acetate (50 mL), washed withsaturated aqueous brine (3×25 mL), dried over magnesium sulfate andconcentrated in vacuo. The residue is purified by flash chromatographyto afford an alcohol.

F. To a solution of the alcohol prepared in part E (0.010 mmol) indichloromethane (2 mL) is added trichloroacetyl isocyanate (1.00 mmol).After 30 min, the reaction mixture is diluted with dichloromethane (4mL) and neutral alumina (1 g) is added. The resultant suspension isstirred an additional 4 h. The reaction mixture is filtered and theconcentrated filtrate is chromatographed on silica gel to afford acarbamate.

G. Analog 86.

A solution of the carbamate prepared in part F (0.010 mmol) in 48%hydrofluoric acid-acetonitrile (1:9, 2 mL) is stirred at ambienttemperature. After 12 h, saturated aqueous sodium bicarbonate (25 mL) isadded and the mixture is extracted with ethyl acetate (3×20 mL). Thecombined organics are dried over magnesium sulfate and concentrated invacuo. The residue is purified by flash chromatography to afford 86.

Aldol (−)-5: PMB protection: p-Methoxybenzyl alcohol (200 g, 1.45 mol)was added to a suspension of NaH (60% in mineral oil; 5.82 g, 0.146 mol)in anhydrous ether (450 mL) over 1 h at room temperature. The mixturewas stirred 1 h further and cooled to 0° C. Trichloroacetonitrile (158mL, 1.58 mol) was then introduced over 80 min. After 1.5 h the solutionwas concentrated with the water bath temperature maintained below 40° C.The residue was treated with a mixture of pentane (1.5 L) and MeOH (5.6mL), stirred at room temperature for 30 min, and filtered through ashort Celite column. Concentration gave the trichloroimidate (370.9 g)as a yellow oil which was used without further purification.

A solution of Roush's ester (+)-6 (129.0 g, 1.09 mol) inCH₂Cl₂/cyclohexane (1:2, 1.5 L) was cooled to 0° C. and treated withcrude trichloroimidate (370.9 g) and PPTS (13.69 g, 55.0 mmol) over 0.5h. After 3 h, the mixture was warmed to room temperature, stirred for 40h, and concentrated. Suction filtration through a short silica plug(5×6″ sintered glass funnel; 20% ethyl acetate/hexanes) afforded thecorresponding PMB ether (234.2 g) as a pale yellow oil which was dividedinto two portions for the next reaction.

Reduction: A solution of the above PMB ether(116.1 g) in anhydrous THF(800 mL) was cooled to 0° C. and added via cannula to a solution ofLiAlH₄ (0.67 M in THF, 800 mL, 0.536 mol) over 1 h (150 mL THF rinse),warmed gradually to room temperature, and stirred for 1 h. The reactionmixture was cooled to 0° C. and quenched via dropewise addition of H₂O(20 mL), 15% NaOH (20 mL), then H₂O (60 mL). The resultant mixture wasthen treated with MgSO₄ (10 g), filtered (100 mL Et₂O rinse), andconcentrated, furnishing a red oil (91.0 g). The remaining 118.1 g wasprocessed using the same protocol to yield an additional 94 g, yieldinga total of 185 g of the corresponding alcohol (+)-8, which was dividedinto three portions for the next two reactions.

Swern: A solution of DMSO (72.1 mL, 1.02 mol) in CH₂Cl₂ (1.5 L) wascooled to −78° C. and oxalyl chloride (44.3 mL, 0.51 mmol) was addedover 30 min (internal temp ≦−65° C.). After an additional 30 min, asolution of the above alcohol (71.2 g, 0.338 mol) in CH₂Cl₂ (100 mL) wasadded dropwise via cannula down the side of the flask over 30 min (20-mLrinse). The resultant mixture was stirred 45 min further at −78° C.,then i-Pr₂NEt (345 mL, 2.03 mol) was added over 45 min. The mixture wasstirred 30 min further at −78° C. then slowly warmed to 0° C. (internaltemp) via removal of the external cooling bath. The reaction wasquenched via addition to a vigourously stirred aqueous NaHSO₄ solution(1.0 M, 2.0 L). The layers were separated, the aqueous phase extracted(3×Et₂O). The combined organic layers were concentrated (30° C. waterbath), diluted with ether (1000 mL), washed with aqueous NaHSO₄, (3×),water (1×), saturated aqueous NaHCO₃ (1×), and brine (1×). The combinedorganic layers were dried over MgSO₄, filtered and concentrated to givethe corresponding aldehyde (70.5 g, ca. 100%) as a colorless oil.

Evans Aldol Reaction: A solution of oxazolidinone 61 (90.7 g, 389 mmol)in degassed CH₂Cl₂ (972 mL, 4 Å MS dried, argon sparged) was cooled to−55° C. (internal temp) and n-Bu₂BOTf (1.0 M in CH₂Cl₂, 403 mL) wasintroduced over 0.5 h, followed by addition of NEt₃ (61.3 mL, 440 mmol)over 20 min. The mixture was warmed to 0° C. (internal temp), stirredfor 10 min, and cooled to −70° C. A degassed solution of above aldehyde(70.5 g, 0.338 mmol) in CH₂Cl₂ (200 mL) was then added via a cannuladown the side of the flask over 1 h (20 mL rinse). After an additional1.0 h at −78° C., the reaction was warmed to −8° C., stirred for 1 h,then quenched with pH 7 potassium phosphate monobasic-sodium hydoxidebuffer (0.05 M, 220 mL). A solution of 30% H₂O₂ in MeOH (1:2, 700 mL)was added to the vigorously stirred reaction mixture at such a rate asto maintain an internal temp <8° C. (60 min, −10° C. cooling bath). Thereaction was stirred 10 h at room temperature, and concentrated to ca.1000 mL. The residue was dissolved in 1500 mL of 10:1 Et₂O/CH₂Cl₂, andthe resulting layers were separated. The aqueous layer was extracted(3×10:1 Et₂O/CH₂Cl₂), and the combined organic layers were washed withsaturated aqueous NaHCO₃ (1000 mL), water (1000 mL) and saturated brine(2×500 mL). The organic layer was dried over MgSO₄, filtered andconcentrated 35 to ca. 400 mL (3× using a 2000 mL rb). The resultingwhite solid was filtered and dried overnight to give analytically pure62 (83.8 g, 56%). The combined mother liquors were concentrated andrecrystallized from Et₂O to give an additional 10.0 g (7.0%, total yieldof 63%) of 62. The remaining 120 g of precursor alcohol was processedthrough the above two steps to give an additional 155.4 of 62 for atotal of 249.2 g (52% yield over 4 steps). X-ray quality crystals weregrown by recrystallization from ether-hexanes: mp 111.5-113.0 C; [α]²³,_(D) +34.3°; IR (CHCl₃) 3600-3400 (br), 1780, 1705 cm⁻¹; ¹H NMR (500MHz, CDCl₃) δ 7.42-7.33 (m, 3 H) 7.28-7.21 (m, 4 H), 6.85 (m, 2 H), 5.59(d, J=6.9 Hz, 1 H), 4.72 (quintet, J=6.6 Hz, 1 H), 4.43 (s, 2 H), 3.92(qd, J=6.8, 3.4 Hz, 1 H), 3.88 (dd, J=8.2, 3.4 Hz, 1 H), 3.76 (s, 3 H),3.69 (br s, OH), 3.55 (m, 2 H), 1.95 (m, 1 H), 1.20 (d, J=6.9 Hz, 3 H),0.95 (d, J=7.0 Hz, 3 H), 0.88 (d, J=6.6 Hz, 3 H); ¹³C NMR (125 MHz,CDCl₃) δ 175.9, 159.3, 152.8, 133.3, 129.8, 129.4, 128.77, 128.7, 125.6,113.8, 78.9, 75.6, 74.7, 73.2, 55.2, 55.1, 40.9, 36.0, 14.3, 13.6, 9.6;high resolution mass spectrum (CI) m/z 441.2133, [(M)+, calcd forC₂₅H₃₁NO₆Na: 441,2151] . Anal. Calcd for C₂₅H₃₁NO₆: C, 68.01; H, 7.08;N: 3.17. Found: C, 68.29; H, 7.17; N, 3.16.

Common Precursor (−)-5: At 0° C., a suspension ofN,O-dimethylhydroxylamine hydrochloride (50.8 g, 521 mmol) in THF (380mL) was cautiously treated with AlMe₃ (2.0 M in hexane, 256 mL, 512mmol) over 30 min. The resultant solution was stirred 30 min at 0° C.and 90 min at ambient temperature, and then cooled to −20° C. A solutionof oxazolidinone 62 (76.7 g, 174 mmol) in THF (380 mL) was introducedover 60 min via a cannula (20-mL rinse). After an additional 90 min at−20° C., the solution was poured slowly into a solution of aqueous HCl(1.0 N, 1.0 L) and CH₂Cl₂ (1.0 L) and stirred vigorously at 0° C. for 90min. The aqueous phase was extracted with CH₂Cl₂ (3×1L) and the combinedorganic solutions were washed with water (2×500 mL) and saturated brine(500 mL), dried over MgSO₄, filtered and concentrated. The crudematerial was dissolved in a minimal amount of ether. An equal volume ofhexanes was added, and the resultant solution was refrigerated (4° C.)overnite. Filtration of the crystals afforded(4R,5S)-4-methyl-5-phenyl-2-oxazolidinone (30.68 g, 100%). Concentrationof the residual liquid and flash chromatography (20% acetone/hexanes)afforded (−)-5 (55.5 g, 98% yield) as a colorless oil: [α]²³,_(D) —−3.6°(c 1.67, CHCl₃); IR (CHCl₃) 3470, 1680 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ7.25 (d, J=8.6 Hz, 2 H), 6.86 (d, J=8.7 Hz, 2 H), 4.44 (ABq, J_(AB)=11.6Hz, Δ_(AB)=17.1 Hz, 2 H), 3.95 (d, J=2.8 Hz, 1 H), 3.79 (s, 3 H), 3.70(ddd, J=8.2, 3.2, 3.2 Hz, 1 H), 3.66 (s, 3 H), 3.62 (dd, J=9.0, 4.0 Hz,1 H), 3.53 (dd, J=9.1, 5.9 Hz, 1 H), 3.17 (s, 3 H), 3.04 (m, 1 H),1.91-1.84 (m, 1 H), 1.17 (d, J=7.0 Hz, 3 H), 0.98 (d, J=6.9 Hz, 3 H);¹³C NMR (125 MHz, CDCl₃) δ 178.0, 159.0, 130.6, 129.1, 113.7, 113.6,73.8, 72.8, 72.6, 61.3, 55.1, 36.5, 36.0, 14.2, 10.4; high resolutionmass spectrum (CI, NH₃) m/z 326.1962 [(M+H)⁻; calcd for C₁₇H₂₆NO₅:326.1967].

Anal. Calcd for C₁₇H₂₇NO₅: C, 62.74; H, 8.36. Found: C, 62.74; H, 8.24.

Fragment A:

PMP Acetal (+)-11: At −10° C., a vigorously stirred solution of commonprecursor (−)-5 (21.55 g, 66.2 mmol) and powdered 4 Å molecular sieves(25 g) in CH₂Cl₂ (500 mL) was treated with DDQ (17.80 g, 78.4 mmol). Theresultant mixture was warmed to 0° C. over 90 min and filtered through apad of Celite (CH₂Cl₂, 500 mL). The filtrate was washed with aqueousNaOH (1 N, 200 mL), concentrated to ca. {fraction (1/10)} volume,diluted with hexanes (400 mL), washed with aqueous NaOH (2×100 mL) andsaturated brine (2×200 mL), dried over MgSO₄, filtered and concentratedto afford a pale yellow-colored solid. Crystallization fromhexanes-ether afforded (+)-6 as colorless needles (15.90 g). Flashchromatography (25% ethyl acetate/hexanes) of the mother liquor providedan additional 2.50 g of (+)-11 (86% total yield): mp 92.0-93.5° C.;[α]²³, _(D) +36.4° (c 0.73, CHCl₃); IR (CHCl₃) 3010, 1663, 1620 cm⁻¹; ¹HNMR (500 MHz, CDCl₃) δ 7.41 (d, J=8.8 Hz, 2 H), 6.87 (d, J=8.8 Hz, 2 H),5.46 (s, 1 H), 4.04 (dd, J=11.3, 4.7 Hz, 1 H), 3.82 (dd, J=9.8, 6.5 Hz,1 H), 3.79 (s, 3 H), 3.71 (s, 3 H), 3.51 (apparent t, J=11.2 Hz, 1 H),3.19 (s, 3 H), 3.21-3.14 (m, 1 H), 1.98-1.92 (m, 1 H), 1.27 (d, J=7.0Hz, 3H), 0.75 (d, J=6.8 Hz, 3 H); ¹³C NMR (125 MHz, CDCl₃) δ 175.8,159.8, 131.2, 127.2, 113.5, 100.7, 82.8, 72.8, 61.3, 55.3, 39.0, 33.8,32.6, 13.1, 12.4; high resolution mass spectrum (CI, NH₃) m/z 323.1736[M⁺; calcd for C₁₇H₂₅NO₅: 323.1732]. Anal. Calcd for C₁₇H₂₅NO₅: C,63.14; H, 7.79. Found: C, 63.18; H, 7.74.

Aldehyde (+)-12. A solution of amide (+)-11 (16.4 g, 50.7 mmol) in THF(10 mL) was added via cannula over 15 min to a −60° C. solution ofLiAlH₄ (3.09 g, 81.4 mmol) in THF (400 mL). The resultant solution wasstirred 2 h at −60° C., warmed 0° C., stirred 60 min, and quenched viadropwise addition of glacial acetic acid (15.0 mL, 254 mmol), over 45min. Saturated aqueous sodium potassium tartrate (500 mL) was added, andthe resultant solution was vigorously stirred at ambient temperature.After 1 h, the reaction mixture was diluted with hexanes (500 mL), andthe organic layer was separated and concentrated to ca. ½ volume invacuo. The aqueous layer was extracted with CH₂Cl₂ (2×250 mL), and thecombined organic layers were washed with water (200 mL), saturated brine(2×200 mL), and saturated NaHCO₃ (200 mL) The organic solution was dried(MgSO₄), filtered, and concentrated to give (+)-11 as a white slurry(14.4 g) that was used without further purification. An analyticalsample was obtained by recrystallization from ether: mp 68-71° C.;[α]²³, _(D) +16.2° (c 1.02, CHCl₃); IR (CHCl₃) 1735, 1725 cm⁻¹; ¹H NMR(500 MHz, CDCl₃) δ 9.74 (apparent s, 1 H), 7.32 (d, J=8.8 Hz, 2 H), 6.84(d, J=8.7 Hz, 2 H), 5.46 (s, 1 H), 4.13 (dd, J=11.5, 4.8 Hz, 1 H), 4.05(dd, J=10.4, 2.6 Hz, 1 H), 3.77 (s, 3 H), 3.56 (apparent t, J=11.1 Hz, 1H), 2.56 (qd, J=7.1, 2.6 Hz, 1 H), 2.15-2.03 (m, 1 H), 1.23 (d, J=7.1Hz, 3 H), 0.80 (d, J=6.7 Hz, 3 H); ¹³C NMR (125 MHz, CDCl₃) δ 204.0,159.9, 130.7, 127.2, 113.5, 100.9, 81.6, 72.8, 55.2, 47.4, 30.3, 11.9,7.1; high resolution mass spectrum (CI, NH₃) m/z 265.1432 [(M+H)⁺; calcdfor C₁₅H₂₁O₄: 265.1439]. Anal. Calcd for C₁₅H₂₀O₄: C, 68.16; H, 7.63.Found: C, 67.84; H, 7.50.

Aldol (−)-13. A solution of oxazolidinone (−)-9 (17.8 g, 76.2 mmol) inCH₂Cl₂ (100 mL) was cooled to 0° C. and n-Bu₂BOTf (1.0 M in CH₂Cl_(2,)70.85 mL) was added over 0.5 h, followed by addition of NEt₃ (12.9 mL,92.7 mmol) over 20 min. The mixture was stirred at 0° C. for 1 h andcooled to −78° C. A solution of aldehyde (+)-12 (14.4 g) in CH₂Cl₂ (20mL) was added over 10 min, and the mixture was stirred 20 min further at−78° C., warmed to 0° C. and stirred for 1 h. The reaction was quenchedwith pH 7 potassium phosphate monobasic-sodium hydroxide buffer (0.05 M,100 mL) and MeOH (300 mL) and cautiously treated with 30% H₂O₂ in MeOH(100 mL) at 0° C. with stirring. After 1 h, saturated aqueous Na₂S₂O₃(100 mL) was added. Following concentration and extraction with ethylacetate (3×250 mL), the combined extracts were washed with saturatedaqueous Na₂S₂O₃, aqueous 10% NaHCO₃, brine (200 mL each), dried (MgSO₄),filtered and concentrated. Flash chromatography (10% ethylacetate/hexanes) provided (−)-13 (20.9 g, 77%, two steps) as a whitesolid: mp 98-100° C.; [α]²³,_(D) −13.5 (c 1.19, CHCl₃); IR (CHCl₃) 3690,3520 (br),1790, 1695 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.35 (d, J=8.7 Hz,2 H), 7.31 (d, J=7.6 Hz, 2 H), 7.27 (d, J=7.2 Hz, 1 H), 7.19 (d, J=7.7Hz, 2 H), 6.84 (d, J=8.7 Hz, 2 H), 5.45 (s, 1 H), 4.67-4.62 (m, 1 H),4.14 (apparent d, J=5.3 Hz, 2 H), 4.08 (dd, J=11.4, 4.8 Hz, 1 H), 4.07(apparent t, J=4.1 Hz, 1 H), 4.04-3.99 (m, 1 H), 3.76 (s, 3 H), 3.61(dd, J=9.9, 2.2 Hz, 1 H), 3.51 (apparent t, J=11.1 Hz, 1 H), 3.33 (d,J=1.3 Hz, 1 H), 3.21 (dd, J=13.4, 3.4 Hz, 1 H), 2.76 (dd, J=13.4, 9.4Hz, 1 H), 2.12-2.06 (m, 1 H), 1.92-1.86 (m, 1 H), 1.31 (d, J=6.9 Hz, 3H), 1.07 (d, J=7.0 Hz, 3 H), 0.74 (d, J=6.7 Hz, 3 H); ¹³C NMR (125 MHz,CDCl₃) δ 177.1, 160.0, 152.7, 135.0, 131.0, 129.4, 128.9, 127.40,127.39, 113.6, 101.2, 85.8, 74.5, 73.0, 66.0, 55.2, 54.9, 39.8, 37.7,35.7, 30.4, 12.8, 11.7, 7.8; high resolution mass spectrum (CI, NH₃) m/z497.2410 [M⁺; calcd for C₂₈H₃₅NO₇: 497.2413]. Anal. Calcd for C₂₈H₃₅NO₇:C, 67.58; H, 7.09. Found: C, 67.42; H, 7.02.

TBS Ether (−)-14: A solution of alcohol (−)-13 (26.3 g, 52.9 mmol) and2,6-lutidine (11.1 mL, 95.3 mmol) in CH₂Cl₂ (150 mL) was cooled to −20°C. and TBSOTf (20.5 mL, 79.3 mmol) was added over 30 min. After anadditional 2 h at 0° C., the mixture was diluted with ether (300 mL),washed with aqueous NaHSO₄ (1.0 M) and brine (200 mL each), dried overMgSO₄, filtered and concentrated. Flash chromatography (gradientelution, 10%

ethyl acetate/hexanes) afforded (−)-13 (32.4 g, 100% yield) as acolorless oil: [α]²³,_(D) −20.3° (c 1.32, CHCl₃); IR (CHCl₃) 1788, 1705cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.38 (d, J=8.7 Hz, 2 H), 7.30-7.12 (m, 5H), 6.82 (d, J=8.7 Hz, 2 H), 5.44 (s, 1 H), 4.30 (ddt, J=13.4, 7.3, 5.1,1 H), 4.11 (dd, J=7.1, 4.0 Hz, 1 H), 4.02 (dd, J=11.2, 4.7 Hz, 1 H),3.97 (dq, J=7.0, 7.0 Hz, 1 H), 3.80 (dd, J=8.9, 2.3 Hz, 1 H), 3.740(apparent t, J=4.9 Hz, 1 H), 3.738 (s, 3 H), 3.48 (apparent t, J=11.1Hz, 1 H), 3.27 (apparent t, J=8.2 Hz, 1 H), 3.15 (dd, J=13.4, 3.2 Hz, 1H), 2.59 (dd, J=13.4, 9.8 Hz, 1 H), 2.05 (apparent qd, J=7.4, 4.2 Hz, 1H), 2.02-1.94 (m, 1 H), 1.19 (d, J=6.9 Hz, 3 H), 1.04 (d, J=7.5 Hz, 3H), 0.92 (s, 9 H), 0.73 (d, J=6.7 Hz, 3 H), 0.05 (s, 3 H), 0.04 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 175.6, 159.9, 152.4, 135.5, 132.0, 129.4,128.8, 127.8, 127.2, 113.4, 100.7, 80.7, 74.6, 73.1, 65.3, 55.3, 55.2,41.4, 40.9, 37.4, 30.6, 26.0, 18.1, 15.0, 12.7, 11.5, −4.0, −4.6; highresolution mass spectrum (CI, NH₃) m/z 612.3340 [(M+H)⁺; calcd forC₃₄H₅₀NO₇Si: 612.3356]. Anal. Calcd for C₃₄H₄₉NO₇Si: C, 66.74; H, 8.07.Found: C, 66.69; H, 7.98.

Alcohol (+)-15 At −30° C., a solution of imide (−)-14 (32.0 g, 52.3mmol) in THF (600 mL) was treated with EtOH (6.14 mL, 105 mmol). LiBH₄(2.0 M in THF, 52.3 mL, 105 mmol) was then added over 15 min. After anadditional 1 h at 0° C. and 12 h at room temperature, the mixture wasdiluted with ether (1.0 L), quenched carefully with aqueous NaOH (1.0 N,200 mL), and stirred at room temperature for 2 h. The layers wereseparated, and the organic phase was washed with brine (500 mL), driedover Na₂SO₄, filtered and concentrated. Flash chromatography (20% ethylacetate/hexanes) provided (+)-15 (18.7 g, 81% yield) as a colorless oilthat solidified upon standing. An analytical sample was obtained byrecrystallization from hexane: mp 65.0-67.0° C.; [α]²³,_(D or) [α]_(D)²³=+36.4° (c 1.57, CHCl₃); IR (CHCl₃) 3630, 3480 (br) cm⁻¹; ¹H NMR (500MHz, CDCl₃) δ 7.36 (d, J=8.7 Hz, 2 H), 6.85 (d, J=8.8 Hz, 2 H), 5.38 (s,1 H), 4.08 (dd, J=11.2, 4.7 Hz, 1 H), 3.84 (dd, J=6.7, 1.9 Hz, 1 H),3.77 (s, 3 H), 3.53 (dd, J=9.9, 1.8 Hz, 1 H), 3.55-3.52 (m, 1 H), 3.47(apparent t, J=11.1 Hz, 1 H), 3.44 (dd, J=10.3, 6.2 Hz, 1 H), 2.08-1.97(m, 2 H), 1.94 (dqd, J=7.1, 7.1, 1.7 Hz, 1 H), 1.76 (br s, 1 H), 1.02(d, J=7.1, 3 H), 0.88 (s, 9 H), 0.84 (d, J=6.9 Hz, 3 H), 0.73 (d, J=6.7Hz, 3 H), 0.03 (s, 3 H), 0.00 (s, 3 H); ¹³C NMR (125 MHz, CDCl₃) δ159.8, 131.4, 127.3, 113.5, 101.0, 82.9, 74.3, 73.3, 66.3, 55.2, 38.7,37.8, 30.7, 26.1, 18.3, 12.2, 11.1, 10.7, −4.0, −4.2; high resolutionmass spectrum (CI, NH₃) m/z 439.2889 [(M+H)⁺; alcd for C₂₄H₄₃O₅Si:439.2879]. Anal. Calcd for C₂₄H₄₂O₅Si: C, 65.71; H, 9.65. Found: C,65.51; H 9.54.

Iodide (+)-A. A vigorously stirred solution of alcohol (+)-15 (4.70 g,10.7 mmol), triphenylphosphine (4.21 g, 16.1 mmol) and imidazole (1.09g, 16.1 mmol) in benzene/ether (1:2, 75 mL) was treated with iodine(4.08 g, 16.1 mmol). After 1 h, the mixture was diluted with ether (200mL), washed with saturated Na₂S₂O₃ and brine (100 mL each), dried overMgSO₄, filtered and concentrated. Flash chromatography (2% ethylacetate/hexanes) furnished (+)-A (5.56 g, 95% yield) as a colorless oilthat solidified on standing. Recrystallization from ethanol affordedcolorless needles: mp 43-44° C.; [α]²³,_(D) +51.3° (c 1.22, EtOH); ¹HNMR (500 MHz, CDCl₃) δ 7.39 (d, J=8.7 Hz, 2 H), 6.86 (d, J=8.8 Hz, 2 H),5.40 (s, 1 H), 4.09 (dd, J=11.2, 4.7 Hz, 1 H), 3.85 (dd, J=7.1, 1.9 Hz,1 H), 3.79 (s, 3 H), 3.48 (dd, J=8.2, 1.5 Hz, 1 H), 3.47 (apparent t,J=11.1 Hz, 1 H), 3.18-3.12 (m, 2 H), 2.11-2.00 (m, 2 H), 1.84 (dqd,J=7.1, 7.1, 1.6 Hz, 1 H), 1.02 (d, J=7.1 Hz, 3 H), 0.98 (d, J=6.7 Hz, 3H), 0.89 (s, 9 H), 0.72 (d, J=6.7 Hz, 3 H), 0.06 (s, 3 H), 0.04 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 159.8, 131.4, 127.4, 113.4, 100.9, 82.4,75.5, 73.2, 55.3, 39.6, 38.7, 30.7, 26.2, 18.4, 14.7, 14.5, 12.2, 10.7,

3.7,

3.8; high resolution mass spectrum (CI, NH₃) m/z 548.1833 [M⁺; calcd forC₂₄H₄₁IO₄Si: 548.1819]. Anal. Calcd for C₂₄H₄₁O₄ISi: C, 52.55; H, 7.53.Found: C, 52.77; H, 7.68.

Fragment B:

TBS Ether (−)-17: A solution of common precursor (−)-5 (48.0 g, 148mmol) and 2,6-lutidine (30.1 mL, 258 mmol) in CH₂Cl₂ (370 mL) was cooledto −20° C. (1:1 acetone/water) and tert-butyldimethylsilyltrifluoromethanesulfonate (38.6 mL, 168 mmol) was added over 20 min. Themixture was stirred for 1.5 h, diluted with cold Et₂O (800 mL, 0° C.),poured into 300 mL of 1 M NaHSO₄, and the resulting layers wereseparated

The aqueous layer was extracted (3×Et₂O), and the combined organiclayers were washed with aqueous1.0 M NaHSO₄ (4×), water, saturatedNaHCO₃ (2×), and brine. The organic layer was dried over MgSO₄, filteredand concentrated to yield (−)-17 (65.1 g, 100%, purity>95% by ¹H NMR) asa clear, colorless oil. An analytical sample was prepared via flashchromatography (10% ethyl acetate/hexanes): [α]²³,_(D) −9.5° (c 1.84,CHCl₃); IR (CHCl₃) 1658 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.21 (d, J=8.7Hz, 2 H), 6.83 (d, J=8.7, 2 H) 4.36 (ABq, J_(AB)=11.6 Hz, Δ_(AB)=17.3Hz, 2 H), 3.92 (dd, J=8.2, 3.0 Hz, 1 H), 3.77 (s, 3 H), 3.55 (s, 3 H),3.54 (dd, J=9.2, 2.5 Hz, 1 H), 3.13 (dd, J=9.2, 7.8 Hz, 1 H), 3.09 (s, 3H), 3.15-3.09 (m, 1 H), 1.92-1.87 (m, 1 H), 1.09 (d, J=7.0 Hz, 3 H),0.98 (d, J=7.0 Hz, 3 H), 0.88 (s, 9 H), 0.04 (apparent s, 6 H); ¹³C NMR(125 MHz, CDCl₃) δ 176.8, 159.1, 130.9, 129.2, 113.7, 76.0, 72.7, 71.9,61.1, 55.2, 39.3, 38.9, 26.1, 18.4, 15.3, 15.0, −3.87, −3.93; highresolution mass spectrum (CI, NH₃) m/z 440.2823 [(M+H)⁺; calcd forC₂₃H₄₂NO₅Si: 440.2832].

Anal. Calcd for C₂₃H₄₁NO₅Si: C, 62.83; H, 9.40. Found: C, 63.05; H,9.32.

Aldehyde (−)-18: At −78° C., a solution of amide (−)-17 (9.19 g, 20.9mmol) in THF (750 mL, dried over 4 Å MS) was treated with DIBAL-H (1.0 Min hexane, 115.0 mL) via dropwise addition down the sides of the flask(30 min addition time). The reaction was stirred for an additional 3 hand quenched with MeOH (8 mL). The −78° C. reaction mixture was pouredinto saturated aqueous Rochelle's salt (1000 mL) and diluted with Et₂O(1500 mL). After stirring at rt for 30 min, the mixture was poured intoa separatory funnel and virourously shaken to break up the emulsion. Thelayers were separated, and the combined organic layers were washed withsaturated aqueous Rochelle's salt, water, saturated NaHCO₃ and brine(2×300 mL each). The organic layer was dried over MgSO₄, filtered andconcentrated to give (−)-18 (31 g, 100%) as a clear, colorless oil,which was taken on to the next step without further purification. Ananalytical sample was obtained via flash chromatography (10% ethylacetate/hexanes): [α]²³,_(D) −22.9° (c 1.50, CHCl₃); IR (CHCl₃) 1730cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 9.67 (d, J=0.9 Hz, 1 H), 7.22 (d, J=8.7Hz, 2 H), 6.86 (d, J=8.7 Hz, 2 H), 4.37 (ABq, J_(AB)=11.6 Hz,Dn_(AB)=23.6 Hz, 2 H), 4.18 (dd, J=6.1, 3.7 Hz, 1 H), 3.78 (s, 3 H),3.41 (dd, J=9.2, 5.7 Hz, 1 H), 3.31 (dd, J=9.2, 6.0 Hz, 1 H), 2.47 (qdd,J=7.1, 3.7, 0.9 Hz, 1 H), 2.03-1.95 (m, 1 H), 1.08 (d, J=7.0 Hz, 3 H),0.94 (d, J=7.0 Hz, 3 H), 0.84 (s, 9 H), 0.04 (s, 3 H), −0.03 (s, 3 H);¹³C NMR (125 MHz, CDCl₃) δ 204.8, 159.2, 130.5, 129.2, 113.8, 72.7,72.4, 71.7, 55.3, 50.0, 38.3, 25.9, 18.2, 14.3, 8.4, −4.1, −4.4; highresolution mass spectrum (FAB, NBA) m/z 403.2304 [(M+Na)⁺; calcd forC₂₁H₃₆O₄SiNa: 403.2280].

Fragment B (+)-3: At −23° C., a suspension of EtPh₃PI (68.7 g, 164 mmol,dried at 70° C./0.2 Torr for 2 h) in THF (600 mL, dried over 4 Å MS,sparged with argon) was treated with n-BuLi (2.5 M in hexane, 64.0 mL,160.1 mmol) over 30 min to form a dark red solution. After an additional10 min, the red ylide solution was added over 40 min via cannula to acooled (−78° C.) solution of 12 (41.7 g, 164.2 mmol) in THF (1400 mL,solution prepared by adding 12 to degassed THF at rt and vigorouslystirring for 40 min before cooling) such that the internal temperaturedoes not exceed −70° C. The resultant yellow slurry was stirred at −75°C. (internal) for 5 min and warmed to −23° C. (internal). NaHMDS (1.0 Min THF, 147 mL) was added via cannula over 30 min, and the resultingorange suspension was stirred 15 min further and cooled to −33° C.(internal). A solution of crude aldehyde (−)-13 (31.2 9, 82.1 mmol) inTHF (200 mL) was introduced via cannula over 15 min, and the reactionmixture as stirred at −30° C. for an additional 45 min, warmed to 7° C.over 1 h, and quenched with MeOH (20 mL). Following concentration andsuction filtration through a 6×8″ silica plug (100% Et₂O,2000 mL suctionfiltration sintered glass frit), the filtrate was washed with saturatedaqueous Na₂S₂O₃ and brine, dried over MgSO₄, filtered and concentrated.Flash chromatography (15% CHCl/hexanes; then gradient elution 1% ethylacetate/hexanes 32% ethyl acetate/hexanes) furnished (+)-3 (19.6 g, 46%yield for two steps, 9:1 Z/E) as a clear, colorless oil). An analyticalsample of the Z isomer was obtained by reversed-phase HPLC (gradientelution; 90% CH₃CN/H₂O

100% CH₃CN): colorless oil; [α]²³,_(D) +23° (c 0.30, CHCl₃); ¹H NMR (500MHz, CDCl₃) d 7.25 (d, J=8.6 Hz, 2 H), 6.87 (d, J=8.7 Hz, 2 H), 5.28(apparent dd, J=8.9, 1.4 Hz, 1 H), 4.41 (ABq, J_(AB)=7.0 Hz,Dn_(AB)=10.2 Hz, 2 H), 3.80 (s, 3 H), 3.60 (apparent t, J=5.3 Hz, 1 H),3.51 (dd, J=9.1, 5.1 Hz, 1 H), 3.23 (dd, J=9.0, 8.0 Hz, 1 H), 2.54-2.47(m, 1 H), 2.44 (d, J=1.4 Hz, 3 H), 2.00-1.92 (m, 1 H), 1.00 (d, J=6.9Hz, 3 H), 0.95 (d, J=6.7 Hz, 3 H), 0.89 (s, 9 H), 0.02 (s, 3 H), 0.01(s, 3 H); ¹³C NMR (125 MHz, CDCl₃) d 159.1, 139.6, 131.0, 129.1, 113.7,98.9, 76.5, 72.6, 72.5, 55.3, 44.5, 38.7, 33.5, 26.1, 18.4, 14.7, 14.5,−3.95, −3.99; high resolution mass spectrum (FAB, NBA) m/z 541.1626[(M+Na)⁺; calcd for C₂₃H₃₉IO₃SiNa: 541.1611].

FRAGMENT C: Aldehyde (−)-27: A mixture of PMB ether (−)-5 (4.27 g, 9.71mmol), Pearlman's catalyst (20% Pd(OH)₂/C, 1.60 g) and EtOH (120 mL) wasstirred for 9 h under H₂ (balloon) at room temperature, filtered andconcentrated. The resulting alcohol (−)-13 (3.84 g, containingp-methoxyanisole) was used without further purification. At 0° C., asolution of crude alcohol(3.84 g) and Et₃N (6.4 mL, 46 mmol) in CH₂Cl₂(24 mL) and DMSO (48 mL) was treated with SO₃.pyridine (5.7 g, 36 mmol).After 90 min, the mixture was diluted with ether (150 mL), washed withH₂O (100 mL), aqueous NaHSO₄ (1.0 M, 100 mL), H₂O (100 mL) and brine(100 mL), dried over MgSO₄, and concentrated. Flash chromatography (20%ethyl acetate/hexanes) afforded (−)-27 (2.88 g, 93% yield) as acolorless oil that solidified on standing at 0° C. Recrystallization(hexanes) afforded colorless plates: mp 45-46° C.; [C]²³,_(D) −65.0° (c1.38, CHCl₃); IR (CHCl₃) 1750, 1720 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 9.68(d, J=1.6 Hz, 1 H), 4.22 (dd, J=8.9, 2.6 Hz, 1 H), 3.68 (s, 3 H), 3.10(apparent s, 4 H), 2.46 (qdd, J=7.1, 2.6, 1.5 Hz, 1 H), 1.16 (d, J=6.9Hz, 3 H), 1.10 (d, J=7.0 Hz, 3 H), 0.88 (s, 9 H), 0.092 (s, 3 H), 0.088(s, 3 H); ¹³C NMR (125 MHz, CDCl₃) δ 203.2, 175.6, 75.1, 61.5, 52.1,39.6, 32.1, 25.9, 18.2, 15.4, 10.2, −4.07, −4.11; high resolution massspectrum (CI, NH₃) m/z 318.2096 [(M+H)⁺; calcd for C₁₅H₃₂NO₄Si:318.2100].

Enone (−)-64: To a −78° C. solution of diisopropylamine (14.24 mL, 104.1mmol) in THF (77 mL) was added n-BuLi (2.5M in hexanes, 43 mL, 107.6mmol). The mixture was slowly warmed to −30° C. over 30 min, stirred at0° C. for 15 min, then cooled to −78° C. Neat mesityl oxide was thenadded (7.94 mL, 69.4 mmol), stirred for 5 min, followed by dropwiseaddition of trimethylsilylchloride (15.51 mL, 122.19 mmol). The mixturewas stirred 5 min, quenched with 15 mL saturated NaHCO₃ solution, anddiluted with 50 mL pentane. The mixture was washed (H₂O), separated, andthe aqueous layer was extracted with pentane (2×30 mL). The combinedorganic extracts were dried (MgSO₄), filtered, and concentrated.Distillation (70° C. @ 30 Torr) provided 7.55 g (15:1 mixture) of 63 asa clear oil.

To a −78° C. solution of aldehyde (−)-27 (7.15 g, 22.5 mmol) in CH₂Cl₂(50 mL) was added (dropwise over 20 min) TiCl₄ (1M in CH₂Cl₂, 22.7 mL,22.7 mmol). The resultant solution was stirred 10 min at −78° C., thenneat 63 (4.67 g, 27.4 mmol) was added dropwise over 2 min (rinse 2×5 mL)and the reaction mixture was further stirred at −78° C. for 2 h. Thesolution was next poured into a solution comprised of pH 8 phosphatebuffer (130 mL) and saturated aqueous NaHCO₃ solution (66 mL) andstirred for 10 min. The aqueous layer was seperated and extracted withCH₂Cl₂ (2×250 mL). The combined organic layers were washed (H₂O, 250mL), diluted (hexanes, 200 mL) and treated with 1 mL of trifluoroaceticacid. The solution was stirred 10 min at ambient temperature, dried(MgSO₄), filtered, and concentrated. Flash chromatography (gradientelution, 1-10% EtOAc/hexanes) afforded (−)-64 (5.72 g, 72%) as a whitesolid: mp 53-55° C.; [α]²³,_(D) −10.6° (c 0.88, CHCl₃); IR (CHCl₃) 1728,1719, 1695 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 6.09 (m, 1 H), 4.78 (ddd,J=10.0, 6.6, 4.3 Hz, 1 H), 3.65 (t, J=2.8 Hz, 1 H), 2.72 (dd, J=15.8,4.3 Hz, 1 H), 2.66 (dd, J=15.8, 6.7 Hz, 1 H), 2.62 (qd, J=7.6, 3.2 Hz, 1H), 2.13 (d, J=1.1 Hz, 3 H), 2.07 (dqd, J=10.0, 6.8, 2.4 Hz, 1 H), 1.87(d, J=1.2 Hz, 3 H), 1.25 (d, J=7.6 Hz, 3 H), 0.97 (d, J=6.8 Hz, 3 H),0.87 (s, 9 H), 0.05 (s, 3 H), 0.04 (s, 3 H); ¹³C NMR (125 MHz, CDCl₃) δ196.9, 173.6, 156.8, 124.1, 77.8, 74.3, 47.0, 43.9, 33.6, 27.7, 25.7,20.9, 18.0, 16.1, 13.8, −4.5, −4.7; high resolution mass spectrum (ES)m/z 377.2127 [(M+Na)⁺; calcd for C₁₉H₃₄O₄SiNa: 377.2124]

Alcohol (−)-65: A solution of enone (−)-64 (6.0 g, 16.9 mmol) in toluene(170 mL) was cooled to −78° C. and treated with K-Selectride′ (1.0 M inTHF, 19.5 mL, 19.5 mmol). After 3 h, the mixture was added to a solutioncontaining pH 7.0 buffer (100 mL), H₂O₂ (10 mL, 10% in MeOH), andglacial AcOH (2 mL). The resulting solution was stirred for 45 min atambient temperature. The aqueous layer was extracted with CH₂Cl₂ (4×200mL) and the combined organics were dried (MgSO₄), filtered, andconcentrated. Flash chromatography (15% ethyl acetate/hexanes, 1% ACOH)afforded (−)-65 (3.09 g, 51%) as a colorless oil that solidified onstanding. Recrystallization (hexanes) afforded colorless needles: mp77.5-78.5° C.; [α]²³,_(D) −21.1° (c 2.02, CHCl₃); IR (CHCl₃) 3620,3400-3600 (br), 1725 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 5.21 (apparent dt,J=8.6, 1.3 Hz, 1 H), 4.75 (br t, J=9.1 Hz, 1 H), 4.60 (td, J=9.9, 2.3Hz, 1 H), 3.67 (t, J=3.0 Hz, 1 H), 2.66 (qd, J=7.5, 3.4 Hz, 1 H), 1.90(dqd, 9.7, 6.8, 2.6 Hz, 1 H), 1.83 (ddd, J=14.5, 9.9, 2.4 Hz, 1 H), 1.71(d, J=1.1 Hz, 3 H), 1.70 (d, J=1.2 Hz, 3 H), 1.65 (br s, 1 H), 1.60(ddd, J=14.5, 10.1, 2.9 Hz, 1 H), 1.26 (d, J=7.6 Hz, 3 H), 0.99 (d,J=6.7 Hz, 3 H), 0.89 (s, 9 H), 0.08 (s, 3 H), 0.07 (s, 3 H); ¹³C NMR(125 MHz, CDCl₃) δ 174.0, 134.8, 127.7, 77.8, 74.2, 64.1, 43.7, 41.5,34.6, 25.7, 25.6, 18.2, 17.9, 16.0, 13.7, −4.6, −4.8.

Anal. Calcd for C₁₉H₃₆O₄Si: C, 64.00; H, 10.18. Found: C, 63.92; H,10.43.

TBS Ether (−)-66: A solution of alcohol (−)-65 (3.09 g, 8.67 mmol) andimidazole (1.92 g, 28.2 mmol) in DMF (44 mL) was cooled to 0° C. andtreated with tert-butyldimethylsilyl chloride (2.41 mg, 16.0 mmol). Theresultant solution was stirred 12 h at ambient temperature, diluted withether (75 mL), washed with H₂O (2×100 mL) and saturated brine (100 mL),dried over MgSO₄, and concentrated. Flash chromatography (5% ethylacetate/hexanes) afforded (−)-19 (3.55 g, 87%) as a colorless oil:[α]²³,_(D) −20.6° (c 0.80, CHCl₃); IR (CHCl₃) 1718 cm⁻¹; ¹H NMR (500MHz, CDCl₃) δ 5.11 (apparent dt, J=8.6, 1.3 Hz, 1 H), 4.71 (ddd, 10.4,8.7, 2.2 Hz, 1 H), 5.55 (td, J=10.4, 1.7 Hz, 1 H), 3.65 (t, J=2.7 Hz, 1H), 2.63 (qd, J=7.6, 3.0 Hz, 1 H), 1.83 (dqd, 10.0, 6.8, 2.5 Hz, 1 H),1.74 (ddd, J=14.2, 10.5, 1.8 Hz, 1 H), 1.68 (d, J=1.1 Hz, 3 H), 1.65 (d,J=1.2 Hz, 3 H), 1.44 (ddd, J=14.2, 10.6, 2.3 Hz, 1 H), 1.26 (d, J=7.6Hz, 3 H), 0.98 (d, J=6.7 Hz, 3 H), 0.89 (s, 9 H), 0.85 (s, 9 H), 0.07(s, 3 H), 0.06 (s, 3 H), 0.05 (s, 3 H), 0.01 (s, 3 H); ¹³C NMR (125 MHz,CDCl₃) d 173.9, 131.6, 129.1, 77.4, 74.6, 65.2, 44.0, 42.8, 34.4, 25.9,25.7, 25.6, 18.3, 18.1, 18.0, 16.4, 14.0, −4.3, −4.5, −4.8, −4.9; highresolution mass spectrum (EI) m/z 469.3156[(M−H)⁺; calcd forC₂₅H₅₀O₄Si₂: 469.3156]

Fragment (−)-C: A solution of olefin (−)-66 (570 mg, 1.20 mmol) inCH₂Cl₂ (20 mL) was cooled to −78° C. and treated with a stream of ozoneand oxygen until the colorless solution became steel-blue in appearance.The reaction mixture was purged with a stream of argon for 40 min,followed by the cautious addition of triphenylphosphine (349 mg, 1.3mmol). The cooling bath was removed, and the solution was stirred atambient temperature for 1 h, concentrated, and chromatographed (20%ethyl acetate/hexanes) to afford (−)-67 (508 mg, 94%) as a colorless oilthat solidified upon standing at 5° C. Recrystallization from hexanesafforded an analytical sample: mp 58-60° C.; [α]²³, _(D) −55.5.° (c1.46, CHCl₃); IR (CHCl₃) 1730 (br) cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 9.67(br s, 1 H), 4.52 (td, J=10.5, 2.1 Hz, 1 H), 4.46 (dd, J=10.5, 3.5 Hz, 1H), 3.67 (t, J=2.3 Hz, 1 H), 2.66 (qd, J=7.6, 2.6 Hz, 1 H), 1.95-1.84(m, 3 H), 1.77 (ddd, J=14.1, 10.5, 2.1 Hz, 1 H), 1.27 (d, J=7.6 Hz, 3H), 0.99 (d, J=6.7 Hz, 3 H), 0.92 (s, 9 H), 0.89 (s, 9 H), 0.13 (s, 3H), 0.11 (s, 3 H), 0.08 (s, 3 H), 0.07 (s, 3 H); ¹³C NMR (125 MHz,CDCl₃) δ 203.2, 173.1, 76.0, 74.7, 73.7, 44.2, 36.2, 34.1, 25.72, 25.66,18.1, 17.9, 16.5, 14.0, −4.55, −4.63, −4.9, −5.2; high resolution massspectrum (CI) m/z 445.2793 [(M+H)⁺; calcd for C₂₂H₄₅O₅Si₂: 445.2806]

(+)-39 (Modified Negeshi Coupling): A 1.0 M solution of anhydrous ZnCl₂(20 mL, 19.93 mmol) was added via syringe to a solution of alkyl iodide(+)-A (10.93 g, 19.93 mmol) in dry Et₂O (80 mL), and the resultingsolution was degassed (2 freeze-pump thaw cycles). The solution wascooled to −78° C., and t-BuLi (1.7 M in pentane, 35.2.0 mL, 59.8 mmol)was added via cannula over 12 min. The resultant solution was stirred 5min further, evacuated and purged (1×0.1 Torr). The −78° C. bath wasremoved, and the reaction was stirred at ambient temperature for 1 h.The resulting cloudy suspension was transfered by cannula into a mixtureof vinyl iodide (+)-B (8.98 g, 17.3 mmol; 9:1 Z/E) and Pd(PPh₃)₄ (1.0 g,0.87 mmol) The reaction mixture was covered with aluminum foil, stirredovernight, and quenched via slow addition of the reaction mixture towater (200 mL). The mixture was diluted with Et₂O, and the layers wereseparated. The water layer was extracted (3×Et₂O) and the combinedorganic layers were washed [saturated aqueous NaHCO₃, brine), dried(MgSO₄), filtered and concentrated. Flash chromatography (gradientelution; 2% EtOAc/hexanes R 5% or to EtOAc/hexanes] gave a white waxthat was recrystrallized from 75 mL of ethanol to afford (+)-39 [9.3 g(two crops), 66% yield; 73% based on purity of vinyl iodide] as whiteneedles: mp 81.0-81.5° C.; [α]²³,_(D) +28.6° (c 1.12, CHCl₃); ¹H NMR(500 MHz, CDCl₃) d 7.36 (d, J=8.7 Hz, 2 H), 7.22 (d, J=8.6 Hz, 2 H),6.86 (d, J=9.0 Hz, 2 H), 6.84 (d, J=8.9 Hz, 2 H), 5.37 (s, 1 H), 5.00(d, J=10.2 Hz, 1 H), 4.36 (ABq, J_(AB)=11.6 Hz, Dn_(AB)=17.4 Hz, 2 H),4.08 (dd, J=11.2, 4.7 Hz, 1 H), 3.78 (s, 3 H), 3.77 (s, 3 H), 3.61 (dd,J=7.1, 1.8 Hz, 1 H), 3.51 (dd, J=9.9, 1.7 Hz, 1 H), 3.47 (apparent t,J=11.0 Hz, 1 H), 3.46 (dd, J=9.1, 5.0 Hz, 1 H), 3.38 (dd, J=6.0, 4.8 Hz,1 H), 3.19 (apparent t, J=8.8 Hz, 1 H), 2.51 (ddq, J=10.1, 6.5, 6.5 Hz,1 H), 2.32 (apparent t, J=12.2 Hz, 1 H), 2.08-2.02 (m, 1 H), 1.99-1.93(m, 2 H), 1.88 (dqd, J=7.1, 7.1, 1.8 Hz, 1 H), 1.67 (br d, J=11.1 Hz, 1H), 1.55 (d, J=0.5 Hz, 3 H), 1.01 (d, J=7.1 Hz, 3 H), 0.94 (d, J=6.9 Hz,3 H), 0.90 (s, 9 H), 0.89 (d, J=6.7 Hz, 3 H), 0.87 (s, 9 H), 0.74 (d,J=6.3 Hz, 3 H), 0.73 (d, J=6.4 Hz, 3 H), 0.03 (s, 3 H), 0.013 (s, 3 H),0.008 (s, 3 H), 0.003 (s, 3 H); ¹³C NMR (125 MHz, CDCl₃) δ 159.8, 159.0,132.0, 131.5, 131.2, 131.1, 129.0, 127.3, 113.7, 113.5, 101.1, 83.4,78.49, 78.46, 73.3, 72.6, 72.5, 55.3, 38.8, 38.2, 37.5, 35.6, 33.7,30.8, 26.27, 26.25, 23.1, 18.42, 18.40, 17.0, 14.6, 12.6, 12.1, 10.9,−3.5, −3.7, −3.8, −3.9; high resolution mass spectrum (FAB, NBA) m/z835.5315 [(M+Na)⁺; calcd for C₄₇H₈₀O₇Si₂Na: 835.5341]. Anal. Calcd forC₄₇H₈₀O₇Si₂: C, 69.41; H, 9.91. Found: C, 69.52; H, 10.10.

Alcohol (+)-40 (Chemoselective Hydrolysis of PMB Ether): At 0° C., asolution of PMB ether (+)-39 (10.6 g, 12.95 mmol) in CH₂Cl₂ (124 mL) wastreated with H₂O (6 mL) and DDQ (3.18 g, 13.99 mmol) and stirred for 3h. The mixture was quenched with 20 mL saturated NaHCO₃, washed with H₂O(4×) and seperated. The aqueous layer was then extracted with CH₂Cl₂(2×). The combined organic extracts were then dried (MgSO₄), filteredand concentrated from hexanes to provide an amorphous white solid.Recrystallization (250 mL EtOH) provided (+)-40 (7.31 g) as whiteneedles. The mother liquors were then treated with NaBH₄ (200 mg), andthe reaction mixture concentrated, diluted with CH₂Cl₂, washed withaqueous saturated ammonium chloride and brine. The organic layer wasdried over NaSO₄, decanted, concentrated and chromatographed (5%EtOAc/hexanes) to provided an additional 560 mg of (+)-40 as a whitesolid (7.87 g total, 88%): mp 99-100° C.; [α]²³,_(D) +26.5° (c 0.95,CHCl₃); IR (CHCl₃) 3520 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.36 (d, J=8.7Hz, 2 H) 6.86 (d, J=8.8 Hz, 2 H), 5.37 (s, 1 H), 5.01 (d, J=10.1 Hz, 1H), 4.09 (dd, J=11.2, 4.7 Hz, 1 H), 3.79 (s, 3 H), 3.65 (dd, J=10.4, 4.7Hz, 1 H), 3.63 (dd, J=7.0, 1.8 Hz, 1 H), 3.54-3.50 (m, 1 H), 3.51 (dd,J=10.0, 2.0 Hz, 1 H), 3.47 (apparent t, J=11.2 Hz, 1 H), 3.41 (dd,J=6.6, 4.0 Hz, 1 H), 2.59 (ddq, J=13.2, 6.7, 6.7 Hz, 1 H), 2.33(apparent t, J=12.2 Hz, 1 H), 2.24 (apparent t, J=5.5 Hz, 1 H),2.09-1.95 (m, 2 H), 1.89 (dqd, J=7.0, 7.0, 1.7 Hz, 1 H), 1.84-1.77 (m, 1H), 1.72 (br d, J=11.0 Hz, 1 H), 1.58 (d, J=0.8 Hz, 3 H), 1.01 (d, J=7.1Hz, 3 H), 0.98 (d, J=7.1 Hz, 3 H), 0.94 (d, J=6.7 Hz, 3 H), 0.910 (s, 9H), 0.905 (s, 9 H), 0.75 (d, J=7.1 Hz, 3 H), 0.74 (d, J=7.1 Hz, 3 H),0.09 (s, 3 H), 0.07 (s, 3 H), 0.05 (s, 3 H), 0.01 (s, 3 H); ¹³C NMR (125MHz, CDCl₃) δ 159.8, 133.0, 131.5, 130.5, 127.3, 113.4, 101.0, 83.3,81.6, 78.4, 73.3, 65.4, 55.3, 38.5, 38.2, 37.6, 37.0, 33.7, 30.8, 26.17,26.16, 23.2, 18.4, 18.3, 17.4, 15.7, 12.6, 12.1, 10.9,

3.57,

3.61,

3.66,

3.9; high resolution mass spectrum (CI, NH₃) m/z 693.4918 [(M+H)⁺; calcdfor C₃₉H₇₃O₆Si₂: 693.4945]. Anal. Calcd for C₃₉H₇₂O₆Si₂: C, 67.58; H,10.47. Found: C, 67.20; H, 10.39.

Trityl Protected Anisylidene Acetal (+)-87:

To a solution of alcohol (+)-40 (8.16 g, 11.8 mmol) in pyridine (118 mL)were added trityl chloride (6.90 g, 24.8 mmol) and DMAP (3.02 g, 24.8mmol). The mixture was then refluxed for 18 h, cooled to ambienttemperature, and added to a solution of 1M citric acid (500 mL). Themixture was extracted with CH₂Cl₂ (3×100 mL), washed with 1 M citricacid (2×100 mL) H₂O (100 mL) and saturated NaHCO₃ solution (100 mL). Theorganic solution was separated, dried (NaSO₄), filtered, andconcentrated in vacuo. Flash chromatography (5% EtOAc/hexanes) provided(+)-87 (10.38 g, 94%) as a white foam: [α]²³,_(D) +16.7° (c 0.30,CHCl₃); IR (CHCl₃) 2980, 2880, 1620, 1255 cm⁻¹; ¹H NMR (500 MHz, C₆D₆) δ7.62 (d, J=8.69 Hz, 2 H), 7.60 (d, J=8.09 Hz, 6 H), 7.15 (dd, J=8.8, 6.6Hz, 6 H), 7.04 (apparent t, J=7.4 Hz, 3 H), 6.84 (d, J=8.7, 2 H), 5.43(s, 1 H), 5.06 (d, J=9.9 Hz, 1 H), 3.95 (dd, J=4.6, 11.0, 1 H), 3.77 (d,J=7.1 Hz, 1 H), 3.53 (m, 3 H), 3.48 (dd, J=5.2, 8.6, 1 H), 3.24 (s, 3H), 3.00 (apparent t, J=8.9 Hz, 1 H), 2.72 (m, 1 H), 2.49 (apparent t,J=12.3 Hz, 1 H) 2.41 (m, 1 H), 2.19 (m, 1 H), 1.98 (m, 1 H), 1.92 (m, 2H), 1.75 (apparent d, J=12.1 Hz, 1 H), 1.61 (s, 3 H), 1.23 (d, J=6.8 Hz,3 H), 1.16 (d, J=7.0 Hz, 3 H), 1.14 (d, J=6.7 Hz, 3 H), 1.04 (s, 9 H),0.98 (d, J=6.8 Hz, 3 H), 0.95 (s, 9 H), 0.42 (d, J=6.6 Hz, 3 H), 0.01(s, 3 H), 0.08 (s, 3 H), 0.07 (s, 3 H), 0.03 (s, 3 H); ¹³C NMR (125 MHz,C₆D₆) δ 160.4, 145.2, 132.4, 129.2, 128.3, 128.0, 127.9, 127.1, 113.8,101.8, 86.9, 83.5, 79.1 (2), 73.3, 66.6, 54.7, 40.7, 38.7, 37.9, 36.3,33.9, 31.0, 26.5, 26.4, 23.2, 18.7, 18.5, 18.3, 14.5, 12.9, 11.9, 11.3,

3.3,

3.5,

3.6,

3.8; high resolution mass spectrum (FAB, NBA) m/z 959.6040 [(M+Na)³⁰;calcd for C₅₈H₈₆O₆Si₂Na: 959.6017].

Trityl protected alcohol (−)-88: To a 0° C. solution of trityl ether(+)-87 (10.38 g, 11.1 mmol) in CH₂Cl₂ (111 mL) was added DIBAL-H (1M inToluene, 33.3 mL, 33.3 mmol). The resulting solution was stirred for 4.5h, quenched via dropwise addition of pH 7.0 buffer (20 mL), then dilutedwith CH₂Cl₂ (100 mL). The mixture was then added to 100 mL of saturatedsodium potassium tartrate solution, extracted with CH₂Cl₂ (4×100 mL),and separated. The organic layer was washed with H₂O (400 mL), dried(MgSO₄), filtered, and concentrated. Flash chromatography (20%EtOAc/hexanes) provided (−)-88 (9.5 g, 91%) as a white foam: [α]²³,_(D)−30° (c 0.05, CHCl₃); IR (CHCl₃) 3500, 2940, 1640, 1035 cm⁻¹; ¹H NMR(500 MHz, CDCl₃) δ 7.42 (dd, J=7.9, 1.4 Hz, 6 H), 7.26 (m, 8 H), 7.18(m, 3 H), 6.87 (d, J=8.6 Hz, 2 H), 4.85 (d, J=10.2 Hz, 1 H), 4.52 (d,J=10.5 Hz, 1 H), 4.49 (d, J=10.5 Hz, 1 H), 3.78 (s, 3 H), 3.73 (ddd,J=11.0, 5.2, 3.5 Hz), 3.57 (ddd, J=11.0, 5.5, 5.5 Hz, 1 H), 3.47 (dd,J=5.4, 3.4 Hz, 1 H), 3.38 (dd, J=6.3, 4.4 Hz, 1 H), 3.35 (apparent t,J=5.5 Hz, 1 H), 3.17 (dd, J=8.8, 5.4 Hz, 1 H), 2.74 (aqpparent t, J=8.8Hz, 1 H) 2.42 (m, 1 H), 2.12 (m, 2 H), 1.93 (m, 2 H), 1.84 (m, 1 H),1.48 (apparent d, J=11.0 Hz, 1 H), 1.40 (s, 3 H), 1.38 (m, 1 H), 1.03(d, J=7.0 Hz, 3 H), 1.01 (d, J=6.9 Hz, 3 H), 0.96 (d, J=6.9 Hz, 3 H)0.93 (s, 9 H), 0.86 (J=6.6 Hz, 3 H), 0.82 (s, 9 H), 0.70 (d, J=6.7 Hz, 3H), 0.07 (s, 3 H), 0.02 (s, 3 H),

0.01 (s, 3 H),

0.08 (s, 3 H); ¹³C NMR (125 MHz, CDCl₃) δ 159.4, 144.6, 131.4, 131.0,130.4, 129.3, 128.8 , 127.6, 126.7, 114.0, 86.3, 86.2, 78.2, 77.5, 75.2,66.4, 65.5, 55.3, 40.2, 40.0, 37.5, 36.6, 35.7, 35.0, 26.2, 26.0, 22.9,18.5, 18.2, 17.6, 15.6, 13.7, 13.5, 11.4,

3.4 (2),

3.9,

4.1; high resolution mass spectrum (FAB, NBA) m/z 957.5844 [(M

2H+Na)⁺; calcd for C₅₈H₈₆O₆Si₂Na: 957.5861].

Trityl Protected Triene 90: To a 0° C. solution of alcohol (−)-88 (2.65g, 2.83 mmol) in CH₂Cl₂ (28 mL) were added Dess-Martin periodinane (1.31g, 3.1 mmol) and NaHCO₃ (615 mg, 8.48 mmol). The resulting solution wasstirred for 2.5 h and quenched with saturated NaS₂O₃ solution (15 mL)and saturated NaHCO₃ solution (15 mL). The mixture was then extractedwith Et₂O (3×) and separated. The organic solution was then washed withH₂O, dried (MgSO₄), filtered, and concentrated. The resulting white foam(2.54 g) was used without further purification [89]: IR (CHCl₃) 2960,2850, 1720, 1250 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 9.87 (d, J=2.5 Hz, 1H), 7.54 (d, J=7.5 Hz, 6 H), 7.17 (d, J=8.5 Hz, 2 H), 7.10 (m, 6 H),6.99 (apparent t, 7.3 Hz, 3 H), 6.74 (d, J=8.6 Hz, 2 H), 4.99 (d, J=10.2Hz, 1 H), 4.39 (d, J=10.8 Hz, 1 H), 4.34 (d, J=10.8 Hz, 1 H), 3.56 (dd,J=2.8, 5.8 Hz, 1 H), 3.53 (dd, J=5.3, 5.2 Hz, 1 H), 3.50 (dd, J=6.6, 4.3Hz, 1 H), 3.41 (dd, J=8.6, 5.4 Hz, 1 H), 3.24 (s, 3 H), 2.96 (apparentt, J=8.9 Hz), 2.65 (m, 1 H), 2.51 (m, 1 H), 2.33 (apparent t, J=12.4 Hz,1 H), 1.95 (m, 1 H), 1.89 (m, 1 H), 1.64 (apparent d, J=12.1 Hz, 1 H),1.48 (s, 3 H), 1.18 (d, J=6.9 Hz, 3 H), 1.07 (d, J=4.2, 3 H), 1.05 (d,J=4.6 Hz, 3 H), 0.97 (s, 9 H), 0.96 (s, 9 H), 0.88 (d, J=7.0 Hz, 3 H),0.83 (d, J=6.7 Hz, 3 H), 0.05 (s, 3 H), 0.03 (s, 3 H), 0.026 (s, 3 H),0.01 (s, 3 H); ¹³C NMR (125 MHz, CDCl₃) δ 204.4, 159.3, 144.6, 131.6,131.5, 130.7, 129.5, 129.1 (3), 128.7, 128.0 (3), 127.1, 113.8, 86.3,82.5, 78.2, 77.3, 74.4, 66.4, 55.2, 49.5, 40.3, 40.2, 36.6, 35.7, 34.7,36.2 (3), 26.0 (3), 22.9, 18.5, 18.2, 17.6, 13.7, 13.2, 12.1, 11.4,

3.4 (2),

3.9,

4.1; high resolution mass spectrum (FAB, NBA) m/z 957.5861 [(M+Na)⁺;calcd for C₅BH₈₆O₆Si₂Na: 957.5963].

To a −78° C. solution of allyldiphenylphosphine (1.17 mL, 5.43 mmol) inTHF (17 mL, degassed) was added 3.2 mL of t-butyllithium (1.7M inpentane, 5.43 mmol) and stirred for 5 min. The solution was thenimmersed into a 0° C. bath, stirred for 30 min and cooled to −78° C. Thesolution was treated with Ti(i-OPr)₄ (1.61 mL, 5.43 mmol) and stirredfor 30 min. A precooled (−78° C.) solution of aldehyde 89(2.54 g, 2.72mmol) in THF (10 mL) was added via cannula (rinse 1×2 mL) and stirredfor 1 h, then warmed to 0° C. Iodomethane (1.69 mL, 27.2 mmol) was addedand the solution was warmed to ambient temperature and stirred for 16 h.The solution was quenched with pH 7.0 buffer (20 mL) and extracted withCH₂Cl₂ (3×) and Et₂O (3×). The combined organic layers were washed withsaturated brine solution, dried (MgSO₄), filtered, and concentrated.Flash chromatography (2% EtOAc/hexanes) provided 90 (1.69 g, 62%, 2steps, 8:1 mixture of diastereomers) as a white foam: IR (CHCl₃) 3060,2940, 1600, 1450 cm⁻¹; ¹H NMR (500 MHz, CDCl₃, major dastereomer) d 7.41(d, J=7.2 Hz, 6 H), 7.26 (m, 8 H), 7.18 (apparent t, J=7.25 Hz, 3 H),6.86 (d, J=8.57, 2 H), 6.56 (ddd, J=16.8, 10.7, 10.7 Hz, 1 H), 5.96(apparent t, J=11.0 Hz, 1 H), 5.52 (apparent t, J=10.5 Hz, 1 H), 5.16(d, J=16.8 Hz, 1 H), 5.07 (d, J=10.2 Hz, 1 H), 4.77 (d, J=10.1 Hz, 1 H),4.76 (d, J=10.4 Hz, 1 H), 4.55 (d, J=10.4 Hz, 1 H), 3.80 (s, 3 H), 3.37(dd, J=9.4, 4.5 Hz, 1 H), 3.35 (dd, J=6.6, 4.3 Hz, 1 H), 3.23 (dd,J=7.2, 3.7 Hz, 1 H), 3.13 (dd, J=8.7, 5.5 Hz, 1 H), 2.97 (m, 1 H), 2.73(apparent t, J=8.9 Hz, 1 H), 2.35 (m, 1 H), 2.10 (m, 1 H), 1.90(apparent t, J=12.4 Hz, 1 H), 1.74 (m, 1 H), 1.69 (m, 1 H); ¹³C NMR (125MHz, CDCl₃, major diastereomer) δ 159.1, 144.7, 134.5, 132.2, 131.7,131.3, 130.6, 129.2, 129.1, 128.8, 127.6, 126.8, 117.6, 113.7, 86.3,84.6, 78.2, 75.0, 66.5, 55.3, 40.5, 40.1, 35.9, 35.5, 35.4,35.2, 26.3,26.0, 22.8, 18.6, 18.2, 17.7, 14.7, 14.1, 13.5, 10.5, −3.15, −3.35,−3.97, −4.12; high resolution mass spectrum (FAB, NBA) m/z 981.6225[(M+Na)⁺; calcd for C₆₁H₉₀O₅Si₂Na: 981.6224].

Triene Alcohol 74: Anhydrous MeOH (151 mL) was added to a cold (0° C.)solution of chlorocatecholborane (2.31 g, 14.5 mmol) in 4.5 mL of CH₂Cl₂(3.2 M), and the resulting solution was added in 0.6 mL (1.94 mmol)aliquots at 10 min intervals to a 0.07 M solution of trityl ether 90(1.86 g, 1.94 mmol, 8:1 dr) at 0° until TLC (20% EtOAc/hexanes)indicated ca. 90% reaction completion (total of 2.4 mL of rgt solution,7.74 mmol), at which point the reaction was quenched via dropewiseaddition of 20 mL of saturated NaHCO₃. The resulting mixture was stirredfor 15 min, diluted with 40 mL Et₂O, stirred an additional 30 min, andthe layers were separated. The aqueous layer was extracted (3×Et₂O), andthe resulting organic layers were combined, washed (water and saturatedbrine solution), dried (MgSO₄), filtered, added to 10 g of SiO₂ andconcentrated. Flash chromatography (gradient elution; 5% EtOAc/hexanesto 10% EtOAc/hexanes; 2nd column: 100% CH₂Cl₂; then 20% EtOAc/hexanes)provided 74 (1.20 g, 86%, 8:1 dr) as a white foam and starting ether 90(247 mg, 13%; 99% based on recovered starting material). [α]²³,_(D) +32°(c 0.70, CHCl₃; 12:1 dr); IR (CHCl₃) 3500, 2950, 1620, 1250 cm⁻¹; ¹H NMR(500 MHz, CDCl₃, major diastereomer) δ 7.27 (d, J=8.6 Hz, 2 H), 6.87 (d,J=8.6 Hz, 2 H), 6.61 (ddd, J=16.8, 10.6, 10.6, 1 H), 6.05 (apparent t,J=11.0 Hz, 1 H), 5.58 (apparent t, J=10.6 Hz, 1 H), 5.23 (d, J=16.8 Hz,1 H), 5.12 (d, J=10.3 Hz, 1 H), 4.98 (d, J=10.2 Hz, 1 H), 4.57 (d,J=10.6 Hz, 1 H), 4.45 (d, J=10.5 Hz, 1 H), 3.80 (s, 3 H), 3.66 (ddd,J=10.8, 4.8, 4.5, 1 H), 3.51 (ddd, J=11.0, 5.7, 5.6 Hz, 1 H), 3.45 (dd,J=4.7, 3.9 Hz, 1 H), 3.40 (dd, J=6.9, 3.8 Hz, 1 H), 0.26 (dd, J=7.3, 3.7Hz, 1 H), 3.0 (m, 1 H), 2.56 (m, 1 H), 2.29 (apparent t, J=5.52 Hz, 1H), 2.06 (apparent t, J=12.4 Hz, 1 H), 1.81 (m, 3 H), 1.65 (apparent d,J=11.2 Hz, 1 H), 1.59 (s, 3 H), 1.11 (d, J=6.8 Hz, 3 H), 1.01 (d, J=7.0Hz, 3 H), 0.99 (d, J=7.2 Hz, 3 H), 0.95 (s, 9 H), 0.92 (m, 12 H), 0.72(d, J=6.7 Hz, 3 H), 0.11 (s 9 H), 0.08 (s, 3 H),; ¹³C NMR (125 MHz,CDCl₃, major diastereomer) δ 159.1, 134.5, 132.8, 132.3, 131.2, 130.5,129.2, 129.0, 117.5, 113.7, 84.6, 81.7, 77.1, 75.0, 65.3, 55.3, 40.1,38.5, 36.8, 36.1, 35.4, 35.3, 26.7, 26.3, 26.2, 23.0, 18.7, 18.6, 18.3,17.6, 15.8, 14.6, 10.6, −3.2, −3.4, −3.6, −3.9; high resolution massspectrum (FAB, NBA) m/z 739.5129 [(M+Na)⁺; calcd for C₄₂H₇₆O₅Si₂Na:739.5156].

Phosphonium Salt 75: A solution of iodine (1.07 g, 4.24 mmol) in 10 mLof Et₂O was added dropewise to a vigorously stirred solution of alcohol(+)-74 (1.41 g, 1.97 mmol; 8:1 mix of cis/trans diene isomers), PPh₃(1.37g, 5.22 mmol) and imidazole (342 mg, 5.02 mmol) in benzene/ether(1:1, 40 mL) at 0° C. The resultant cannary yellow suspention wasstirred 30 min at 0° C. and poured into 150 mL of 1:1 water/hexanes. Thelayers were separated and the aqueous layer was extracted with hexanes.The combined organic layers were washed with saturated aqueous sodiummetabisulfite (2×50 mL), water (1×50 mL) and brine (100 mL). The clear,colorless organic layer was dried over MgSO₄, filtered and concentrated.The resulting white slurry was loaded onto a plug of SiO₂ with a minimalamount of CH₂Cl₂ and rapidly eluted off the column (0.05% Et₃N/2%Et₂O/hexanes) to afford the corresponding iodide as colorless oil (8:1ds mixture of diene isomers; contaminated with ca. 20% PPh₄) which wastaken on to the next step without further purification: ¹H NMR (500 MHz,C₆D₆, major diene isomer) δ 7.51 (m, 6 H), 7.43 (d, J=8.6 Hz, 2 H), 7.18(m, 9 H), 6.97 (d, J=8.6 Hz, 2 H), 6.84 (ddd, J=16.8, 10.8, 10.8 Hz, 1H), 6.23 (apparent t, J=10.8 Hz, 1 H), 5.84 (apparent t, J=10.5 Hz, 1H), 5.33 (dd, J=16.8, 1.9 Hz, 1 H), 5.27 (d, J=10.4, 1 H), 5.23 (d,J=10.2 Hz), 4.74 (d, J=10.7 Hz, 1 H), 4.66 (d, J=10.7 Hz, 1 H), 3.76(apparent t, J=4.4 Hz, 1 H), 3.58 (dd, J=6.6, 4.0 Hz, 1 H), 3.48 (m, 2H), 3.46 (s, 3 H), 3.24 (m, 1 H), 3.17 (dd, J=9.6, 8.0 Hz, 1 H), 2.80(m, 1 H), 2.44 (apparent t, J=12.3 Hz, 1 H), 2.17 (m, 1 H), 2.10 (m, 1H), 2.02 (m, 1 H), 1.78 (s, 3 H), 1.38 (d, J=6.9 Hz, 3 H), 1.27 (d,J=6.8 Hz, 3 H), 1.20 (s, 9 H), 1.18 (m, 6 H), 1.10 (s, 9 H), 1.06 (d,J=6.7 Hz, 3 H), 0.33 (s, 3 H), 0.31 (s, 3 H), 0.24 ( s, 3 H), 0.23 ( s,3 H).

To a solution of above Iodide in benzene/toluene (7:3, 5.0 mL) was addeddiisopropylethylamine (0.2 mL, 1.14 mmol) and triphenylphosphine (2.5 g,9.53 mmol). The resulting solution was loaded into a 20 mL polyethylenesyringe and capped in such a way as to eliminate any trapped air (3×1.0mL rinse of 7:3 benzene/toluene solution). The syringe was loaded into ahigh pressure apparatus and subjected to a pressure of 12.8 Kbar. After14 days, the reaction mixture was concentrated and chromatographed(gradient elution, 20% EtOAc/hexanes to 50% EtOAc/hexanes, then 20%MeCN/CH₂Cl₂) to provide 75 as a light yellow solid [1.68 g, 78% yieldfrom alcohol 46; 8:1 dr]: [α]²³,_(D) +22° (c 1.0,CHCl₃); IR (CHCl₃)2940, 1610, 1580, 1250 cm⁻¹; ¹H NMR (500 MHz, CDCl₃, Major isomer) δ7.75 (m, 15 H) 7.27 (d, J=8.6 Hz, 2 H) 6.86 (d, J=8.6 Hz, 2 H), 6.54(ddd, J=16.8, 10.6, 10.6 Hz, 1 H), 5.89 (apparent t, J=11.0 Hz, 1 H),5.50 (apparent t, J=10.5 Hz, 1 H),5.30 (d, J=10.6 Hz, 1 H), 5.12 (d,J=16.8 Hz, 1 H), 5.08 (d, J=10.2 Hz, 1 H), 4.56 (d, J=10.4 Hz, 1 H),4.45(d, J=10.4 Hz, 1 H), 3.78 (s, 3 H), 3.70 (m, 1 H), 3.69 (dd, J=6.7, 4.6Hz, 1 H), 3.42 (dd, J=5.3, 3.1 Hz, 1 H), 3.23 (dd, J=7.9, 3.2 Hz, 1 H),3.19 (m, 1 H), 2.97 (m, 1 H), 2.41 (m, 1 H), 2.03 (m, 1 H), 1.94(apparent t, J=12.2 Hz, 1 H), 1.84 (m, 2 H), 1.57 (m, 1 H), 1.54 (s, 3H), 1.10 (d, J=6.8 Hz, 3 H), 0.96 (d, J=6.8 Hz, 3 H), ) 0.89 (m, 21 H),0.69 (d, J=6.9 Hz, 3 H), 0.66 (d, J=6.7 Hz, 3 H), 0.095 (s, 3 H), 0.08(s, 3 H), 0.04 (s, 3 H), −0.05 (s, 3 H); ¹³C NMR (125 MHz, CDCl₃) δ159.1, 135.3, 135.2, 134.2, 133.5, 133.4, 132.5, 132.3, 131.0, 130.9,130.7, 130.6, 130.4, 129.1, 128.8, 128.2, 118.6, 118.0, 117.6, 113.7,84.6, 80.0, 79.9, 76.8, 75.1, 55.3, 39.8, 35.8, 35.5, 35.3, 35.2, 26.2,26.1 (2), 26.0, 22.6, 18.6, 18.5, 18.2, 17.4, 16.9, 15.0, 10.5, −3.3,−3.4 (2), −4.0; high resolution mass spectrum (FAB, NBA) m/z961.6134[(M−I)⁺; calcd for C₆₀H₉₀O₄PSi₂: 961.6115].

Tetraene 58 (Wittig Coupling): Phosphonium salt 75 (1.20 g, 1.10 mmol;8:1 ratio of diene isomers), was azeotropically dried with benzene(3×1.5 mL) using a double manifold and further dried by heating to 50°C. under vacuum (0.2 torr) for 12 h. The salt was dissolved in 6 mL offreshly distilled THF, sparged with argon for 15 min, and cooled to −20°C. The resultant solution was treated with sodiumbis(trimethylsilyl)amide (1.0 M in THF, 1.04 mL), stirred 15 min, warmedto 0° C., stirred 30 min, and re-chilled to −24° C. To this orange/redsolution was transferred via cannula a degassed solution of aldehyde(−)-67 (508 mg, 1.14 mmol) in THF (3 mL+1×0.5 mL rinse) over 7 min. Theorange solution was allowed to slowly warm to −8° C. over 3.25 h. Theresulting light yellow solution was quenched with saturated NH₄Cl,diluted with Et₂O and H₂O. The layers were separated, and the aqueouslayer was extracted (3×Et₂O). The combined organic layers were dried(Na₂SO₄), concentrated, and chromatographed (gradient elution; 2%EtOAc/hexanes or 50% to EtOAc/hexanes; then 40% CH₃CN/CH₂Cl₂) to affordcis isomer 58 (767 mg, 65%; white foam, 8:1 ratio of diene isomers),transi isomer 58 (50 mg, 4%; clear oil; 8:1 ratio of diene isomers), andphosphonium salt 75 (399 mg, 33%; 8:1 ratio of diene isomers).[enant-(+)-58 [α]²³,_(D) −32+ (c 0.23, CHCl₃)]; IR (CHCl₃) 1725 cm⁻¹; ¹HNMR (500 MHz, CDCl₃, major diene isomer) δ 7.25 (d, J=9.0 Hz, 2 H), 6.84(d, J=8.7 Hz, 2 H), 6.57 (ddd, J=16.7, 10.6, 10.6 Hz, 1 H), 6.00(apparent t, J=11.0 Hz, 1 H), 5.55 (apparent t, J=10.5 Hz, 1 H), 5.26(dd, J=11.1, 7.9 Hz, 1 H), 5.19 (dd, J=15.4, 1.4 Hz, 1 H), 5.18(apparent t J=10.1 Hz, 1 H), 5.10 (d, J=10.2 Hz, 1 H) 5.01 (d, J=10.0Hz, 1 H), 4.75 (apparent t, J=9.2 Hz, 1 H), 4.50 (ddd, J=10.5, 1.3, 1.3Hz, 1 H), 4.50 (ABq, J_(AB)=10.6 Hz, Δ_(AB)=42.6 Hz, 2 H), 3.78 (s, 3H), 3.60 (apparent t, J=2.4 Hz, 1 H), 3.42 (dd, J=5.1, 3.7 Hz, 1 H),3.23 (dd, J=7.5, 3.7 Hz, 1 H), 3.20 (apparent t, J=5.4 Hz, 1 H),3.01-2.94 (m, 1 H), 2.60 (qd, J=7.7, 2.6 Hz, 1 H), 2.62-2.55 (m, 1 H),2.45-2.38 (m, 1 H), 1.98 (apparent t, J=12.3 Hz, 1 H), 1.84-1.67 (m, 3H), 1.63 (br d, J=13.2 Hz, 1 H), 1.52 (s, 3 H), 1.55-1.48 (m, 1 H), 1.20(d, J=7.6 Hz, 3 H), 1.09 (d, J=6.8 Hz, 3 H), 0.98 (d, J=6.8 Hz, 3 H),0.93 (apparent d, J=6.7 Hz, 6 H), 0.93 (s, 9 H), 0.89 (s, 9 H), 0.86 (s,9 H), 0.85 (s, 9 H), 0.84 (d, J=6.8 Hz, 3 H), 0.69 (d, J=6.7 Hz, 3 H),0.085 (s, 3 H), 0.079 (s, 3 H), 0.051 (s, 3 H), 0.046 (s, 3 H), 0.042(s, 3 H), 0.029 (s, 3 H), 0.028 (s, 3 H), −0.02 (s, 3 H); ¹³C NMR (125MHz, CDCl₃) δ 173.2, 159.1, 134.4, 133.4, 132.4, 132.2, 131.9, 131.3,131.2, 129.11, 129.09, 117.6, 113.7, 84.6, 80.5, 76.9, 75.0, 74.9, 64.6,55.3, 44.1, 42.7, 40.1, 37.5, 36.0, 35.44, 35.37, 35.2, 34.2, 26.31,26.28, 25.9, 25.7, 23.0, 18.7, 18.6, 18.4, 18.1, 18.0, 17.1, 16.5, 16.4,14.9, 14.1, 10.5, −3.0, −3.2, −3.3, −4.3, −4.4, −4.5, −4.8, −4.9; highresolution mass spectrum (FAB, NBA) m/z 1149.7836 [(M+Na)⁺; calcd forC₆₄H₁₁₈O₈Si₄Na: 1149.7802].

Alcohol (+)-59: At 0° C., a solution of PMB ether 58 (1.12 g, 0.993mmol, 8:1 mixture of cis/trans diene isomers) in CH₂Cl₂ (10 mL) wastreated with H₂O (0.5 mL) and DDQ (270 mg, 1.19 mmol). The mixture wasstirred for 10 min at 0° C., warmed to rt and stirred an additional 5min. The mixture was quenched with 50 mL saturated NaHCO₃, diluted withCH₂Cl₂ (300 mL), and washed with H₂O (500 mL) and saturated brinesolution (500 mL). The combined organic layers were dried (MgSO₄),filtered and concentrated. Flash chromatography (gradient elution; 4%EtOAc to 20% EtOAc/hexanes) provided (+)-59 (822 mg, 82%) as a whitefoam: [enant-(+)-33 [α]²³, _(D) −20° (c 0.34, CHCl₃)]; IR (film, NaCl)3500 (br), 1740cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 6.61 (ddd, J=16.8, 10.9,10.9 Hz, 1 H), 6.13 (apparent t, J=11.0 Hz, 1 H), 5.32 (apparent t,J=10.5 Hz, 1 H), 5.28 (dd, J=11.1, 7.9 Hz, 1 H), 5.24-5.21 (m, 1 H),5.19 (apparent t, J=10.3 Hz, 1 H), 5.14 (d, J=10.2 Hz, 1 H), 5.06 (d,J=10.0 Hz, 1 H), 4.76 (apparent t, J=9.3 Hz, 1 H), 4.50 (apparent t,J=9.9 Hz, 1 H), 3.62 (apparent t, J=2.4 Hz, 1 H), 3.60 (dd, J=5.5, 3.4Hz, 1 H), 3.32 (br d, J=5.3 Hz, 1 H), 3.24 (apparent t, J=5.1 Hz, 1 H),2.79 (ddq, J=9.9, 6.7, 6.7 Hz, 1 H), 2.60 (qd, J=7.6, 2.7 Hz, 1 H),2.63-2.57 (m, 1 H), 2.50-2.45 (m, 1 H), 2.16 (apparent t, J=12.3 Hz, 1H), 1.90-1.77 (m, 3 H), 1.75-1.69 (m, 2 H), 1.57 (s, 3 H), 1.60-1.50 (m,1 H), 1.20 (d, J=7.6 Hz, 3 H), 0.96 (d, J=6.8 Hz, 3 H), 0.95 (d, J=6.6Hz, 3 H), 0.95-0.93 (m, 6 H), 0.91 (s, 9 H), 0.89 (s, 9 H), 0.89-0.84(m, 3 H), 0.87 (s, 9 H), 0.85 (s, 9 H), 0.73 (d, J=6.8 Hz, 3 H), 0.07(apparent s, 6 H), 0.052 (s, 3 H), 0.051 (s, 3 H), 0.04 (apparent s, 6H), 0.03 (s, 3 H), −0.01 (s, 3 H); ¹³C NMR (125 MHz, CDCl₃) d 173.3,134.7, 133.5, 132.5, 132.1, 132.0, 131.5, 131.0, 118.4, 80.5, 78.8,76.4, 74.9, 64.7, 44.1, 42.7, 38.0, 37.4, 36.3, 36.1, 35.2, 35.1, 34.2,26.3, 26.2, 25.9, 25.7, 23.2, 18.5, 18.1, 18.0, 17.3, 17.2, 16.4, 16.1,14.1, 13.7, 9.4, −3.0, −3.3, −3.6, −4.34, −4.36, −4.5, −4.8; highresolution mass spectrum (FAB, NBA) m/z 1029.7273 [(M+Na)⁺; calcd forC₅₆H₁₁₀O₇Si₄Na: 1029.7226; DDQ Adduct 32: [α]²³,_(D) +47° (c 1.2,CHCl₃)]; IR (CHCl₉) 3225, 2900, 1710, 1580, 1070 cm⁻¹; ¹H NMR (500 MHz,C₆D₆, 1:1 mixture of C21 diastereomers) δ 5.60 (m, 2 H), 5.26 (m, 2 H),5.15 (m, 2 H) 4.75 (apparent t, J=10.5 Hz, 1 H), 4.43 (dd, J=11.6, 1.0Hz, 1 H), 3.47 (m, 2 H), 3.04 (2, 1 H), 2.92 (m, 1 H), 2.80 (m, 1 H),2.73 (m, 1 H), 2.66 (m, 1 H), 2.44 (apparent d, J=9.6 Hz, 1 H), 2.25 (m,2 H), 2.12 (dd, J=17.1, 5.4 Hz, 1 H), 1.86 (m, 7 H), 1.76 (m, 1 H), 1.70(apparent t, J=12.6 Hz, 1 H), 1.24 (d, J=6.8 Hz, 3 H), 1.21 (d, J=6.6Hz, 3 H), 1.15 (d, J=7.6 Hz, 3 H), 1.13 (s, 9 H), 1.08 (s, 9 H), 1.06(s, 9 H), 1.01 (d, J=6.7 Hz, 3 H), 0.94 (s, 9 H), 0.94 (s, 9 H), 0.90(d, J=6.6 Hz, 3 H), 0.84 (d, J=6.8 Hz, 3 H), 0.40 (d, J=6.6 Hz, 3 H),0.34 (s, 3 H), 0.30 (s, 3 H), 0.27 (s, 3 H), 0.26 (s, 3 H), 0.21 (s, 6H), −0.01 (s, 3 H), −0.04 (s, 3 H); high resolution mass spectrum (FAB,NBA) m/z 1255.6598 [(M+Na)⁺; calcd for C₆₄H₁₁₀Cl₂N₂O₉Si₄Na: 1255.6563].

Carbamate (−)-60. A solution of alcohol (+)-59 (822 mg, 0.816 mmol) inCH₂Cl₂ (8.2 mL) was treated with Cl₃CCON═C═O (980 mL, 0.979 mmol) atroom temperature for 30 min. Solution was loaded directly onto neutralAl₂O₃ (1.5×4″ plug). After 4 h, the material was flushed from the Al₂O₃(EtOAc, 500 mL), concentrated, and purified by flash chromatography (10%ethyl acetate/hexanes) providing 786 mg (+)-60 (92%) as a white foam:[enant (+)-60 [α]²³,_(D) −37 (c 0.19, CHCl₃)]; IR (film, NaCl) 3510,3360 (br), 3180, 1730 (br) cm⁻¹; ¹H NMR (500 MHz, CDCl₃) d 6.58 (dddd,J=16.8, 10.6, 10.6, 0.7 Hz, 1 H), 6.01 (apparent t, J=11.0 Hz, 1 H),5.36 (apparent t, J=10.4 Hz, 1 H), 5.27 (dd, J=11.1, 7.9 Hz, 1 H),5.22-5.16 (m, 2 H), 5.12 (d, J=10.1 Hz, 1 H), 5.03 (d, J=10.0 Hz, 1 H),4.76 (apparent t, J=9.2 Hz, 1 H), 4.71 (apparent t, J=6.1 Hz, 1 H), 4.50(ddd, J=10.5, 10.5, 1.3 Hz, 1 H), 4.44 (br s, 2 H), 3.62 (apparent t,J=2.4 Hz, 1 H), 3.42 (apparent t, J=4.5 Hz, 1 H), 3.22 (apparent t,J=5.3 Hz, 1 H), 2.98 (ddq, J=10.1, 6.6, 6.6 Hz, 1 H), 2.60 (qd, J=7.6,2.7 Hz, 1 H), 2.63-2.55 (m, 1 H), 2.48-2.41 (m, 1 H), 2.09 (apparent t,J=12.4 Hz, 1 H), 1.93-1.88 (m, 1 H), 1.87-1.77 (m, 2 H), 1.71 (ddd,J=14.1, 10.8, 1.6 Hz, 1 H), 1.67 (br d, J=13.7 Hz, 1 H), 1.56 (apparents, 3 H), 1.55-1.50 (m, 1 H), 1.21 (d, J=7.6 Hz, 3 H), 0.98 (d, J=6.8 Hz,3 H), 0.95 (d, J=7.0 Hz, 3 H), 0.94 (d, J=7.5 Hz, 3 H), 0.918 (d, J=6.8Hz, 3 H), 0.915 (s, 9 H), 0.89 (s, 9 H), 0.86 (s, 9 H), 0.853 (d, J=6.4Hz, 3 H), 0.847 (s, 9 H), 0.70 (d, J=6.8 Hz, 3 H), 0.09 (s, 3 H), 0.07(s, 3 H), 0.053 (s, 3 H), 0.051 (s, 3 H), 0.040 (s, 3 H), 0.037 (s, 3H), 0.03 (s, 3 H), −0.02 (s, 3 H); ¹³C NMR (125 MHz, CDC1₃) d 173.3,156.9, 133.6, 133.5, 132.4, 132.1, 131.9, 131.4, 129.8, 118.0, 80.5,78.9, 74.9, 64.6, 44.2, 42.7, 37.8, 37.4, 36.0, 35.3, 35.2, 34.5, 34.2,26.3, 26.2, 25.9, 25.7, 23.0, 18.5, 18.4, 18.1, 18.0, 17.5, 17.1, 16.44,16.38, 14.1, 13.7, 10.1, −3.0, −3.4, −3.6, −4.4, −4.5, −4.8; highresolution mass spectrum (FAB, NBA) m/z 1072.7264 [(M+Na)⁺; calcd forC₅₇H₁₁₁NO₈Si₄Na: 1072.7283].

(+)-Discodermolide [1]. Carbamate (+)-60 (202 mg, 0.191 mmol) wasdissolved in MeOH (70 mL) and stirred for 15 min at room temperature.Aqueous hydrochloric acid (3N, 40 mL) was added in 2-4 mL portions over4 hours at a rate which minimized precipitation (ca. 10 to 15 minintervals). An additional 20 mL of 3 N aq HCl was added over 1 h at 15min intervals, and the sides of the flask/stir bar were rinsed with 8 mLof MeOH. After 8 h, an additional 20 mL of 3 N aq HCl was added in oneportion, and the resulting solution was stirred for 2 h at rt, dilutedwith 350 mL of water and poured into 400 mL of EtOAc. The resultinglayers were separated, and the aqueous layer was saturated with NaCl andextracted (3×EtOAc). The combined organic layers were washed withsaturated aqueous NaHCO₃ (2×100 mL) and saturated brine, dried (Na₂SO₄),filtered, and concentrated. Flash chromatography (gradient elution; 5%MeOH/CH₂Cl₂ to 10% MeOH/CH₂Cl₂) gave 1 (107 mg, 93% yield) as a whiteamorphous solid. X-ray quality crystals were obtained by dissolving theamorphous solid in acetonitrile (0.1 M) at rt and allowing the solutionto stand for several hours at rt: mp 108-111°; [α]²³,_(D) +16° (c 0.033,MeOH); IR (CHCl₃) 3690, 3620, 3540, 3430, 1740 cm⁻¹; ¹H NMR (500 MHz,CDCl₃) δ 6.60 (dddd, J=16.8, 8.4, 8.4, 0.8 Hz, 1 H), 6.02 (apparent t,J=11.1 Hz, 1 H), 5.51 (dd, J=11.2, 7.9 Hz, 1 H), 5.42 (ddd, J=10.6,10.6, 0.6 Hz, 1 H), 5.34 (apparent t, J=10.4 Hz, 1 H), 5.20 (dd, J=16.9,1.9 Hz, 1 H), 5.16 (d, J=10.0 Hz, 1 H), 5.11 (d, J=10.1 Hz, 1 H),4.77-4.69 (m, 1 H), 4.70 (dd, J=7.3, 4.2 Hz, 1 H), 4.60 (ddd, J=10.0,10.0, 2.4 Hz, 1 H), 4.56 (br s, 2 H), 3.73 (m, 1 H), 3.28 (m, 1 H), 3.18(dd, J=6.8, 4.8 Hz, 1 H), 2.98 (ddq, J=10.1, 6.9, 6.9 Hz, 1 H), 2.78(ddq, J=9.8, 6.8, 6.8 Hz, 1 H), 2.66 (qd, J=7.3, 4.6 Hz, 1 H), 2.60-2.55(m, 1 H), 2.10-1.80 (m, 10 H), 1.69 (ddd, J=14.4, 10.3, 3.1 Hz, 1 H),1.64 (d, J=1.3 Hz, 3 H), 1.30 (d, J=7.4 Hz, 3 H), 1.06 (d, J=6.9 Hz, 3H), 1.00 (d, J=6.8 Hz, 3 H), 0.99 (d, J=6.7 Hz, 3 H), 0.97 (d, J=6.8 Hz,3 H), 0.94 (d, J=6.8 Hz, 3 H), 0.82 (d, J=6.3 Hz, 3 H); ¹³C NMR (125MHz, CDCl₃) d 173.6, 157.0, 134.4, 133.7, 133.4, 132.9, 132.2, 129.9,129.8, 117.9, 79.1, 78.9, 77.2, 75.7, 73.2, 64.4, 43.1, 41.0, 37.4,36.1, 36.0, 35.8, 35.3, 34.8, 33.1, 23.3, 18.4, 17.4, 15.6, 15.5, 13.7,12.5, 9.0; high resolution mass spectrum (FAB, NBA) m/z 616.3840[(M+Na)⁺; calcd for C₃₃H₅₅NO₈Na: 616.3826].

EXAMPLE 76 Mesylate 1201

To a solution of alcohol 1200 (0.032 mmol) in CH₂Cl₂ (1 mL) was addedtriethylamine (7 μL) and methanesulfonylchlroride (4 μL). After stirringfor 1 hour 1 mL of sodium bicarbonate solution was added and the mixturewas extracted (3×, CH₂Cl₂), dried (MgSO4), filtered, and concentrated.Purification was performed by flash chromatography (25% EtOAc/Hexanes)to provide 29 mg of mesylate 1201 (91%) as a clear oil.

EXAMPLE 77 Isopropyl Adduct 1206

To a 0° C. ethereal solution of mesylate 1201 (0.0269 mmol in 3 mL) wasadded LiAlH4. The mixture was stirred for 45 min. and quenched withRochelle's solution (5 mL). The mixture was stirred for 30 min andextracted with Et2O (2×) and CH₂Cl₂ (2×). The combined organic extractswere washed (Brine), dried (MgSO₄), filtered, and concentrated. Flashchromatography (10% EtOAc/Hexanes) provided 19 mg (80%) of the isopropyladduct 1206 as a yellow oil.

EXAMPLE 78 Propyl Adduct 1202

To a solution of CuI in THF (0.1 M) was added propylmagnesium bromide.The solution was stirred for 1 h and a solution of mesylate 1201 addedvia cannula (THF). The reaction was stirred for 3 hours and quenchedwith sodium bicarbonate solution. The mixture was extracted with Et2O(2×) and CH₂Cl₂ (2×). The combined organic extracts were washed (sodiumbicarbonate, brine), dried (MgSO4), filtered, and concentrated. Flashchromatography was performed (10% EtOAc/Hexanes) to provide the propyladduct 1202.

Those skilled in the art will appreciate that numerous changes andmodifications may be made to the preferred embodiments of the inventionand that such changes and modifications may be made without departingfrom the spirit of the invention. It is therefore intended that theappended claims cover all equivalent variations as fall within the truespirit and scope of the invention.

1. A compound of formula:

wherein: R₁₁ and R₁₂ are each independently C₁-C₁₀ alkyl; R₁₄ and R₁₅are each independently an acid labile hydroxyl protecting group; and R₁₆is H or C₁-C₆ alkyl.
 2. The compound of claim 1 wherein the compound hasthe structure:

wherein TBS is tert-butyldimethylsilyl and TES is triethylsilyl.
 3. Acompound of formula:

wherein: R₇ and R₈ are independently C₁-C₁₀ alkyl; R₆ and R₁₆ areindependently H or C₁-C₆ alkyl; R₉ is an acid labile hydroxyl protectinggroup; and J is:

wherein: R₃₂ is H or C₁-C₆ alkyl; and R₃₃ is an acid labile hydroxylprotecting group.
 4. The compound of claim 3 of formula:

wherein TBS is tert-butyldimethylsilyl and TES is triethylsilyl.
 5. Acompound of formula:

wherein: R₁, R₂, R₇, and R₈ are independently C₁-C₁₀ alkyl; R₃ and R₆are independently selected from hydrogen and C₁-C₆ alkyl; R₄ and R₉ areindependently an acid labile hydroxyl protecting group; R₁₈ is C₆-C₁₄aryl; R₂₅ is an acid stable hydroxyl protecting group; and X is halogen.6. The compound of claim 5 of formula:

wherein TBS is tert-butyldimethylsilyl, Ph is phenyl and PMB ispara-methoxybenzyl.
 7. A compound of formula:

wherein: R₆ is H or C₁-C₁₀ alkyl; R₇ and R₈ are independently C₁-C₁₀alkyl; R₉ is an acid labile protecting group; R₁₈ is C₆-C₁₄ aryl; and Xis halogen.
 8. The compound of claim 7 of formula:

wherein TBS is tert-butyldimethylsilyl and Ph is phenyl.
 9. A compoundof formula:

wherein: R₆ is C₁-C₄ alkyl; R₇ and R₈ are independently C₁-C₁₀ alkyl; R₉is an acid labile hydroxyl protecting group; R₁₀ is an acid stablehydroxyl protecting group; and X is halogen.
 10. The compound of claim 9of formula:

wherein TBS is tert-butyldimethylsilyl and PMB is para-methoxybenzyl.11. A compound of formula:


12. A compound of formula:

wherein: R₁, R₂ and R₃ are independently, C₁-C₁₀ alkyl; X is a halogen;Z₁ and Z₂ are independently, O, S or NR′; R₄ is an acid labile hydroxylprotecting group; R₅ is C₆-C₁₄ aryl; and each R′ is independentlyhydrogen or C₁-C₆ alkyl.
 13. The compound of claim 12 wherein R₁, R₂ andR₃ are methyl; X is iodo; Z₁ and Z₂ are each O; R₄ istert-butyldimethylsilyl; and R₅ is para-methoxyphenyl.